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BRITISH BROADCASTING CORPORATION
RADIO SCIENCE UNIT
CASE NOTES Programme no. 8 - HPV
RADIO 4
TX DATE: TUESDAY 16TH SEPTEMBER 2008 2100-2130
PRESENTER: MARK PORTER
REPORTER: ANNA LACEY
CONTRIBUTORS: ANNE SZARWESKI
JACK CUZICK
MARGARET STANLEY
THOM VAN EVERY
PRODUCER: HELEN SHARP
NOT CHECKED AS BROADCAST
PORTER
Hello. Earlier this month the world's first vaccine against cancer was added to the routine immunisation schedule. As of the start of this school term, every 12 and 13 year old girl will be offered the jab to protect her against infection with two strains of the human papilloma virus, strains that account for around three quarters of all cases of cancer of the cervix.
But it's not just the cancer causing - or oncogenic - properties of HPV that cause us problems, it's also the virus responsible for verrucas and warts, including sexually transmitted genital warts. I'll be meeting a doctor who has set up a pioneering online service that means you can have your genital warts diagnosed and treated without ever having to meet a doctor face to face.
But first the new vaccine and the role that HPV plays in causing cancer of the cervix.
My guest today is Dr Anne Szarweski from Cancer Research UK.
Anne, just remind us of who is going to get the vaccine and when?
SZARWESKI
It's going to be 12 to 13 year old girls and also recently they announced 17 to 18 year old girls this year as well.
PORTER
So there's going to be a catch up programme?
SZARWESKI
Yes, well then next year they're actually going to do a catch up for all the ages in between.
PORTER
So essentially every 12 to 13 year old is going to be offered the jab from now on but if you're under 18 at the moment you will get the jab at some stage?
SZARWESKI
Yes.
PORTER
There are two types of vaccine - can you explain the difference?
SZARWESKI
There's one vaccine which has four virus types in it, two of which are the cervical cancer types and two of which are the genital wart types and that's called Gardasil. And the other vaccine, called Cervarix, which is the one that's been chosen for the vaccination programme, that one has the two cervical cancer types in.
PORTER
Now both jabs are made up of three separate injections, given over what sort of period?
SZARWESKI
Over six months.
PORTER
So you have one at nought, one at a month and one six months later or something like that. Why go for the one that protects against fewer strains because we've chosen the so-called bivalent one, the one that only protects against the strains that cause cancer of the cervix?
SZARWESKI
I think there are a number of reasons and many people have speculated that price was amongst them but we don't actually know that. The reasons that I can see medically are that it looks - the sort of emerging evidence that it looks as though Cervarix may give longer lasting immunity, may possibly give more cross-protection against some of the other cancer causing virus types as well as the two - the main ones in the vaccine. And so there may actually turn out to be some advantages for cervical cancer of Cervarix over Gardasil.
PORTER
And of course if price is an issue it wouldn't be the first time the NHS has chosen something on the basis of price.
SZARWESKI
But in fact longevity is incredibly important because in a vaccination programme whether or not you have to give a booster makes a huge difference to both the cost and the complexity of a programme.
PORTER
Anne, we'll come back to the vaccine a bit later, after a more detailed look at the virus - HPV - that it's designed to protect against. An adversary that has been infecting humans for millennia, and one that comes in many different guises. Jack Cuzick is Professor of Epidemiology at the Wolfson Institute of Preventive Medicine.
CUZICK
Well the viruses were really first identified in the mid '70s, there was some evidence that one of the types of the virus, particularly HPV-6, was causing warts, genital warts, which was known for many, many years but the virus wasn't specifically identified. In the '70s Professor Zur Hausen in Heidelberg identified HPV-16, which proved to be the single most important type for causing cervix cancer.
PORTER
And how many different strains have we identified now?
CUZICK
Oh there's an ongoing list, there are well over a hundred different types now, so it's kind of a stamp collecting activity that people continue to identify new and rare types but in fact there are only a few that really matter.
PORTER
And those that matter what do they actually do to us?
CUZICK
The human papilloma virus is an interesting virus in the sense that it actually - the oncogenic types have produced two proteins, so called E6 and E7, and they interfere primarily with the cell's ability to identify aberrant cells and cause apoptosis and causes cells to die. Normally we have a protein called P53 which is associated with identifying cells that are aberrant and causing them to die. And the virus manages to interfere with this protein and allow the cells that are aberrant to carry on growing and that's why it's a very carcinogenic virus.
PORTER
So put simply: Cells, if they go wrong, have a sort of self-destruct mechanism built into them?
CUZICK
Right.
PORTER
And that's what the virus switches off.
CUZICK
The virus is able to actually switch that off yes.
PORTER
So that results in what - it's linked to cervical cancer - what other sort of problems does it cause?
CUZICK
There are a range of other cancers that it does cause but primarily it's cervix cancer which is the main cancer. So the virus is passed by sexual transmission - it's a venereal virus - and in almost over 90% of the cases the body's able to identify the virus and simply clear it, so the immune system clears over 90% of the infections spontaneously. But for reasons which are still not well understood in a few number of cases the virus manages to establish itself as a persistent infection and when that happens the chances of this progressing to cancer over a period of typically 10 to 20 years are reasonably high.
PORTER
And the strains that are causing that are which ones?
CUZICK
There are 13 well established high risk types, two or three others that are thought to be high risk types, the most important of which is called HPV-16, type 16, which causes about 50% of cancers or so. HPV-18 causes another 15% or so and then there are a number of other high risk types - Type 31, 33, 52, 56 and 58 are also particularly important.
PORTER
What sort of proportion of women will come into contact with the virus and when?
CUZICK
Well almost all sexually active women will be exposed to the virus at some stage, it's really quite a ubiquitous and universal virus and estimates are that by the time a woman is 30 there's about a 70 to 80% chance that she'll have been exposed at some stage. And almost all of these exposures are cleared naturally without any problems at all.
PORTER
But what is it about that small group who don't clear the virus naturally, you said we don't really understand why, are there factors that we can associate with them?
CUZICK
Well I think that's a big challenge at the moment now, it's probably the single most important question in the whole story is that there's this small group of 5 to 10% of the population that do not clear the virus. And we know very little about why that's true. We know that it's almost certainly related to the immune response to the virus, so for example factors like smoking, which do depress the immune system, almost double your risk of actually having a persistent infection going on to cancer. So that's one simple factor. There undoubtedly are more detailed genetic factors in your individual genetic makeup which determine whether you're able to recognise and clear the virus but we don't understand those in any detail at all.
PORTER
Professor Jack Cuzick talking to me at the Wolfson Institute.
You are listening to Case Notes, I'm Dr Mark Porter and I am discussing HPV and the new cancer of the cervix vaccine with my guest Dr Anne Szarweski.
Anne, one of the concerns that has been raised about the new vaccines is that by protecting against the common cancer causing strains 16 and 18, as we heard there, they will encourage through natural selection the emergence of other cancer causing strains, encourage them to mutate and become a problem, therefore making the vaccine less effective. Has that been - have we seen any signs of that yet?
SZARWESKI
No, there's no suggestion of that at all actually in the literature, none at all. And in animal models it doesn't happen. So no I don't think we really need to worry about that.
PORTER
This virus has been around for a long time and it's fairly stable isn't it.
SZARWESKI
That's right.
PORTER
How effective is the vaccine, how good is it at preventing cancer?
SZARWESKI
Well first of all we have to remember that the two strains only account for about three quarters of cervical cancers but then within those the vaccines are just about 100% effective, so they're 100% effective just about against three quarters of cervical cancer.
PORTER
And how long does that protection last for?
SZARWESKI
Well of course we don't know because the trials - the longest we had in the trials is about six and a half years. But certainly for Cervarix, which is - we've got six and a half year data, it's works very well, it's still working very well. And mathematical models have been done looking at sort of antibody levels and so on and they're predicting that it will last probably for at least 20, maybe even 30, years.
PORTER
There's been some adverse publicity in the media linking it to side effects, I've read some pretty scary reports about seizures and paralysis and everything, a lot of people have had this vaccine, what do we know about the side effects from that data?
SZARWESKI
Yeah well my unit was actually involved in the vaccine trials and so I've seen a lot of women and girls being given the vaccine and I can tell you you get a sore arm, you get a sore arm, some of them feel a bit fluish, just like any vaccine, any vaccine you've ever had - sore arm, bit fluish, some people feel a bit shivery and sort of you know - we've not seen anything sort of in the least bit frightening in terms of side effects. And I believe that all these reports of you know the sort of paralysis, the fainting and so on they're actually coincidences rather than actually being caused by the vaccines.
PORTER
What sort of numbers would have been through your unit, what sort of numbers would you have seen?
SZARWESKI
We've had around 200 just in our unit but worldwide there have been like 30,000 women in these trials.
PORTER
And what about since the trials because it's been given to presumably millions of people?
SZARWESKI
Yes it's been rolled out all over the place, in America, in most of Europe, in Australia - they started actually virtually before anybody else. So it's been given to a lot of - lot of - women.
PORTER
And you're saying officially, so far, so good?
SZARWESKI
Well one the things you have to remember about this vaccine it doesn't contain any live virus at all, it's a sort of sham virus, you know, it's a pretend thing, so there's actually no real reason why you should have anything from it because it actually doesn't contain any viral DNA.
PORTER
It's a collection of markers from the outside of the virus effectively.
SZARWESKI
Yes exactly.
PORTER
And what about older women - we heard there that everyone under the age of 18's going to get it but if you had a 19 year old daughter, who's just likely to miss out, would you want her to be vaccinated?
SZARWESKI
She'd be in that clinic tomorrow.
PORTER
We'll come back to that a little bit later.
Your daughter may not be so keen though and we wondered how those 19 to 26 year old women feel about being included? Our reporter Anna Lacey cornered three of them - Line, Lucy and Sam - in a coffee shop in Cambridge, and started by asking them how much they knew about HPV?
SAM
Very little, just - I remember there being a big hoo ha about it a while ago and you can get it via sexually transmitted disease and that's why everybody was so upset about it.
LACEY
And Lucy?
LUCY
Well again I knew a little bit from the research stuff - it can cause genital warts or potentially cervical cancer - but again I don't really know what the mechanisms of it are.
LACEY
And Line did you know that there was a possibility of this vaccine being given to people up to the age of 26?
LINE
No, no absolutely not, I thought it was just 18 from the media coverage.
LACEY
Although these women won't be approached in the current vaccination programme, Professor Margaret Stanley from the Department of Pathology at Cambridge University thinks there's good reason for introducing it in this age group in future.
STANLEY
Nineteen to 26 year olds first of all are highly likely to be infected or become infected with the HPVs that cause cervix cancer and the other HPV diseases of the genital tract. So there is a rationale for vaccinating them. They are sexually active, so there'll be an increased number of women in that age group who have already been exposed and who might be infected. But nonetheless there'll still be a lot of women in that age group who are not.
LACEY
But if you have already been exposed to HPV is the vaccine actually going to help you at all?
STANLEY
If you have been exposed and you've cleared it by your immune response then what the vaccine will do is just simply boost that immune response, so it'll help. But if you're currently infected vaccination will have no influence on what happens to you - it won't alter whether it goes on and becomes something nasty or whether you actually make a good immune response and get rid of the infection.
LACEY
So it seems the worst that can happen is nothing at all. But despite the apparently low risks, would Lucy and the rest of the group have the injection?
LUCY
I'd certainly think about it but I'm not sure that I would immediately jump at the opportunity.
LACEY
And why wouldn't you jump at the opportunity?
LUCY
Because I'm not sure whether or not like how much coverage there is of it, whether it's actually going to protect me and kind of how well it's working yet.
LINE
Absolutely, I'd read more about it before I made my decision. If there are very low risks associated with having the injection then I would definitely be keen to get it.
LACEY
And Sam how do you feel about them bringing it in for people in the older age group?
SAM
I think it's a good thing, we should be allowed to have just as much protection, especially since there's probably a lot of people in that age group who haven't had sex before. So just saying that you'd have to go and put your hands up and say I'm a virgin I want the jab, that it should be available to us and if there's a chance that it could help then I think there's no harm done in having it.
LACEY
There is real concern among gynaecologists that vaccinated women will stop going for cervical screening. And Professor Stanley thinks it's crucial to make clear that the vaccine isn't a perfect alternative.
STANLEY
The real worry is that women might think they've been given a magic bullet. And so if we're going to vaccinate this age group it has to be accompanied by a lot of education and counselling so that they realise they're only protected against two of the HPV types that could cause cancer and they've got to keep coming back for their smears, just in case they get exposed to one of these other types.
LACEY
Screening starts at 25, so 21 year old Sam hasn't yet been asked and they haven't caught up with Line either but Lucy has been for her first screen, albeit reluctantly.
LUCY
Well I wouldn't say I exactly jumped at the chance but I went along with a friend, so it wasn't quite so bad, and I was kind of encouraged by a lot of female friends and relatives that it was a very important thing to do because if you catch it early then it could be treatable.
LACEY
Although the vaccine won't stop the need for screening, it could make the visits less frequent.
STANLEY
Now the way people are thinking is that since HPV testing is so sensitive and if you're HPV negative then we can say with some confidence okay you're alright probably for the next - at least five, probably 10 years. And indeed, as I say, one of the scenarios is that you'll test women at 25, if they're negative you bring them back probably when they're 35, still negative, 45, still negative then maybe leave them for another 20 years but these are all speculations at the minute. In the next 20 years at least the vaccine and the screening programme will work together and if they work together then I think we probably would eliminate cervical cancer in this country.
PORTER
Professor Margaret Stanley talking to Anna Lacey in Cambridge.
Anne, of course the other point that's worth making is that it would also reduce the number of abnormal results that are given to women that unnecessarily worry them.
SZARWESKI
I think that - in this country that's really important because actually our screening programme's so good that we don't have that many women getting cancer but we have hundreds of thousands of women each year having an abnormal smear and virtually all those women are terrified - many of them think they've got cancer when they've just got an abnormal smear. So if we can prevent all that psychological trauma, all that anxiety, because they won't have abnormal smears when they've been vaccinated then that's a huge advantage as well.
PORTER
We heard there about women between the ages of 19 and 26 but what about older women in their late 20s, is it too late for them?
SZARWESKI
It's never too late basically because you never - although we say a woman has a very high risk that eventually during her life she will catch HPV she may not have caught both HPV-16 and 18 for a start because there's you know 15 high risk HPV types and so she may have caught one of the others and you don't know. So she will always benefit, she always has the potential to benefit from this vaccine.
PORTER
But of course as you get older those benefits become less clear cut so it's unlikely that the NHS would ever vaccinate but people - individuals - might choose to do so.
SZARWESKI
Yes I agree, I think you couldn't really justify having women over sort of 25, 26 in the vaccination programme but for individual women if they've got a few hundred pounds to spend - you know I keep seeing adverts for handbags in the weekend magazines for 拢500 for a handbag, which you know I think is insane, but if you want to spend 拢500 on a handbag why not spend that on a cervical cancer vaccine?
PORTER
What about men?
SZARWESKI
Well I personally think it's very important that we should be vaccinating boys as well as girls.
PORTER
Which we're not doing in the UK?
SZARWESKI
Which we're not doing. I think there are two reasons: one is that we want to build up herd immunity, what's called herd immunity, because the vaccine is sexually transmitted, so it's men who are passing it to women. And so we need to vaccinate the boys as well as the girls. Plus of course if we don't vaccinate boys gay men will simply miss out altogether and they are at risk of both warts and anal cancers and other genital cancers and they will have no benefit at all then.
PORTER
But there are no plans at the moment to introduce that?
SZARWESKI
Well at the moment we don't actually have data that it works in men but I think we will quite soon.
PORTER
Briefly, if you're not eligible for routine vaccination how can you get it - you said you have to pay for it, it costs at least 拢300 and you have to go privately presumably?
SZARWESKI
Yes you need to go - there are lots of private clinics now offering the HPV vaccines.
PORTER
And if you were going for it would you choose one version over the other?
SZARWESKI
I think it's very difficult because it depends what you find most important. I think there is a suggestion - an emerging suggestion - that actually Cervarix may well be better for cervical cancer.
PORTER
That's the one that protects against two strains.
SZARWESKI
That's right and it may have longer lasting immunity. And I would think if you're older probably you would want Cervarix because it has the sort of stronger, if you like, adjuvant. But if what you're interested in is getting protection against genital warts and I think if you're a man you would really only want to go for Gardasil because if you're a man the cancer causing strains are not quite so important but you might as well get the benefit of genital warts.
PORTER
While we're talking about genital warts, how big a problem are they in the UK?
SZARWESKI
Genital warts a huge problem, you know we're spending about 拢23 million a year treating them. Hundreds of thousands of people have got genital warts in this country. They may not kill you but they're very distressing - they're unsightly, they cause huge embarrassment, they may take ages to go away and so on. So they're certainly an important problem.
PORTER
Well as Anne said embarrassment is an issue for many people with genital warts, and one reason why some are reluctant to come forward for treatment. Something that a new internet based service hopes to address. Send a digital photograph to the online sexual health clinic Dr Thom and you can get your genital warts diagnosed and treated without ever having to see a doctor or nurse. Dr Thom van Every set up the website.
VAN EVERY
What Dr Thom's trying to do is make it easier for people to look after their sexual health and one of the services we offer is the ability to upload a photograph that you might have taken of your genitals, if you think you have a lesion which could be a wart and a sexual health specialist will look at that photo and then give you advice and possibly treatment, if appropriate, by post, so that you can deal with your problem without having to visit a clinic.
PORTER
Well here's a photo of a man with what looks like, to me, genital warts.
VAN EVERY
Yes I'd agree with that.
PORTER
So explain what we're looking at here.
VAN EVERY
Okay, so we're looking firstly at the picture of a penis and you can see on the fraenulum, which is the skin just underneath the glands of the penis, the end of the penis there is a little cauliflower growth which has several buds to it, if you like.
PORTER
Now you've just zoomed in on there, as you can of course with all digital photos.
VAN EVERY
Exactly and you can see there the sort of cauliflower appearance of it.
PORTER
Yes, the centre of the cauliflower, the sort of white bit of the cauliflower isn't it.
VAN EVERY
Exactly, exactly and also you'll notice that the colour of the pubic hair is grey, just emphasising the age group of people who seem to be using this service.
PORTER
So this gentleman might well be in his 40s.
VAN EVERY
So yes, so this gentleman is 53 years old. I can imagine given the provision of sexual services in this country that he may not feel comfortable sitting in a waiting room with a lot of people who are probably younger than him.
PORTER
So you can tell by looking - now that's pretty obviously warts there.
VAN EVERY
Yeah, I think what's important in this situation is to explain to the patient what the warts are and also I think to remind them of the implication of warts and I think it's very important that your listeners understand that warts - the wart virus is very common, so probably 80% of people who are sexually active have been exposed or have at any one time the wart virus on their body in the genital area. Most people clear the warts themselves with their own immune system but for reasons that aren't always clear probably about 10% of people show warts that we can see. And as doctors really what we're doing is removing the warts that we can see, it's really a cosmetic thing actually, we're not necessarily attempting to totally remove the warts from their body.
PORTER
And actually looking at the views that we've got here, as you can with any digital photograph you're zooming in, you probably get a better view than you do in the consulting room?
VAN EVERY
I think we do and it's not always the case and certainly we ...
PORTER
You're a bit dependent on the quality of .. because you must get some awful pictures.
VAN EVERY
Well we do and so our service has a proviso that if people send us very poor quality photos we will decline to assess it and charge a small admin charge, that's really to stop people sending in silly photos. So patients are asking us to take their problems seriously, we're asking them to take their photographs seriously.
PORTER
Okay, once you make the diagnosis and you're convinced that that's what's going on the next stage is what?
VAN EVERY
Most patients will want treatment for this and there are a variety of treatments that can be used. The most typical treatments are to try and burn the warts off the surface of the skin or there is a separate treatment which modifies the immune system and tries to encourage the immune system to clear it itself. And then there are maybe more drastic treatments where you can actually freeze the warts with cryotherapy and I think a lot of patients in the past have been familiar with the freezing but more often now we're moving to applying either a corrosive substance or this substance that enhances the immune system.
PORTER
So it's a similar sort of management to warts you find elsewhere on the body?
VAN EVERY
I think so, I think so, I think that's right. I think in addition as part of the treatment package we obviously want to encourage people to be screened for other sexual infections, there is an association between having one sexually transmitted infection that we can see in this case and other ones, so that's an important additional feature.
PORTER
Because that's what would happen if you went to a genitourinary medicine clinic - they would want to test you for other things or recommend it anyway.
VAN EVERY
Absolutely and we can offer that service by post as well, so we have further services on our website that allow people to order a postal kit that goes out in the post and women can provide a urine sample, a vaginal swab or men just provide a urine sample.
PORTER
So most of the patients will be opting for what sort of treatment...?
VAN EVERY
Most patients will be opting for the topical treatment, clearly on an online service that does things by post freezing them is not a practical option. So what we have as part of our treatment facility is to, what we call, unhiding treatments to patients. So a patient who came to this service and hadn't been assessed by a doctor would not be able to purchase or ask for treatment. As an online organisation we have a unique status in the UK of being the only one that is authorised and regulated to prescribe online and therefore we do differentiate ourselves from a lot of what we perceive to be cowboys online selling potentially dodgy medication. So these are very legitimate medications.
PORTER
And if you went along to a standard genitourinary medicine clinic you'd be prescribed the same stuff?
VAN EVERY
Absolutely.
PORTER
And you'd be applying it yourself - it's not being done by a professional?
VAN EVERY
Absolutely, I think the only times when it might be applied by somebody else is when it's hard to reach but clearly someone who has a sexual partner could also have that applied by them.
PORTER
One of the things we see in general practice, quite often, is men - young men particularly - coming forward with spots on their penis that they're worried about, the normal sebaceous spots we can reassure them straightaway just at a glance, presumably you must do quite a lot of reassurance as well?
VAN EVERY
Absolutely and I think that part of our service is to reassure people where they are normal and we have an example here of a gentleman who wanted a second opinion on warts that had been diagnosed, he was overseas, he didn't have access to healthcare and he felt uncomfortable just going out and buying or seeking medication in the country he was in. So he sent us a photo of what turned out to be entirely normal spots on his ...
PORTER
So we're looking at a picture of his glands of his penis here and round the base is - at first glance you might think they were warts.
VAN EVERY
Absolutely, so I think this gentleman has a prominent version of normal, of what we call pearly penile papules, which are just skin growths at the base of the penis. They don't need treatment. They often come and go in terms of prominence and we reassured this man that he was entirely normal. And I think one of the advantages of this service is we can get other doctors just to have their opinion on it as well, so this gentleman actually had an additional assessment by a genitourinary dermatologist, which I think is not something a lot of patients can easily access from where they are.
PORTER
So he was pleased to get your e-mail.
VAN EVERY
He was very pleased to get our e-mail.
PORTER
Dr Thom van Every.
Anne, I know many doctors have reservations about online consulting, but this would seem a sensible sort of way of encouraging potentially embarrassed men and women to come at least forward and seek help, that first step.
SZARWESKI
I think it is important what he mentioned though that if you have got one sexually transmitted disease, like genital warts, you may well have another. And so actually it is better to then get tested for sort of everything really.
PORTER
You say may, you're actually quite likely aren't you?
SZARWESKI
Yes probably.
PORTER
We should just clarify of course that having genital warts does not mean that you're necessarily at high risk of developing cancer of the cervix, two different strains.
SZARWESKI
That's right they are different strains. And the viral types that actually cause cervical cancer do not cause warts, so they don't cause any visible changes at all so you wouldn't know you had them.
PORTER
And when you're looking at somebody who's got genital warts you can obviously see them, whether it'll be on the outside of the vagina or on the penis, but what happens when you're looking at the cervix, when they've got the other strains, can you actually see, as somebody doing a smear, any changes?
SZARWESKI
No when you're taking a smear you can't see HPV on the cervix either unless they've actually got a wart on the cervix but the high risk HPV types you can't see a thing.
PORTER
So they're invisible to the naked eye?
SZARWESKI
Absolutely.
PORTER
So what are you looking at or what are the labs looking at when they get the smear, what's the clue that there's a problem?
SZARWESKI
When you have a smear what they're actually looking for is abnormal changes in the cells which are caused by the virus so they're not actually looking on the smear for the virus itself, they're looking for already changes in the cell, so like a stage onward from just having the virus. They're now looking for damage, if you like, that the virus is doing.
PORTER
Anne, thank you very much, I am afraid we must leave it there, Dr Anne Szarweski, thank you very much.
If you would like more information about the new HPV vaccine and the online services mentioned then do visit the Case Notes website at bbc.co.uk/radio4 where you'll find all the required links - and where you can also listen to the programme again or download it as a podcast.
Next week's programme, the last in the current series, is about abortion. How are pregnancies terminated in the 21st Century? Why are so many women having abortions in Britain? And why have recent initiatives to reduce that number seemingly failed to have an impact?
ENDS
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