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Q&A: Prenatal Screening Pioneer Kypros Nicolaides on Introducing Non-invasive Testing in the UK


NicolaidesPhoto2.jpgName: Kypros Nicolaides
Age: 59
Position: Professor of Fetal Medicine, King's College, London University (since 1992) and University College London, London University (since 2009); director, Fetal Medicine Centre and Harris Birthright Research Centre for Fetal Medicine
Experience and Education:
MD, King's College School of Medicine and Dentistry

Kypros Nicolaides, a professor of fetal medicine at King's College and University College London, has been a driving force in developing new techniques and procedures in fetal medicine. In the 1990s, for example, he began studying nuchal translucency, now part of a widely used first-trimester screen for Down syndrome.

This October, Nicolaides started offering Ariosa's non-invasive prenatal Harmony test at the Fetal Medicine Centre, a private clinic he directs that offers ultrasound scans and other pregnancy tests.

He also led several clinical studies of Ariosa's test that involved several thousand women, including a study recently published in the American Journal of Obstetrics and Gynecology that assessed the performance of the test in 2,000 pregnant women undergoing routine first-trimester screening.

Clinical Sequencing News spoke with Nicolaides, who has no financial stake in Ariosa or any other non-invasive prenatal testing company, earlier this month about his experience with the test and how he sees future uptake of testing in the UK. Below is an edited version of the conversation.

How did you get involved in non-invasive prenatal testing, and how did you decide to introduce Ariosa's test routinely in your clinic?

We have been involved in the research element of non-invasive prenatal testing for several years. In the 1990s, a technique that was examined was to isolate fetal cells from the maternal circulation, but that led to a dead end. Subsequently, we collaborated with the group of Dennis Lo [at the Chinese University of Hong Kong], who is a pioneer in the concept of cell-free DNA.

In the last year and a half, we have seen a series of studies that were carried out in high-risk pregnancies that suggested cell-free DNA testing potentially has extremely high performance. Then, we went on to do the study with Ariosa on 2,000 routinely examined patients that demonstrated it is equally applicable to a routine population.

Since October, I was satisfied that all the necessary research had been done, so we started offering the test routinely to our patients at the Fetal Medicine Centre.

How does the test compare to existing screening methods in low-risk populations?

The screening that is carried out at the moment is a combined test, an ultrasound examination to measure the nuchal translucency and a blood test to measure free BHCG and PAPP-A. If you do that, you will classify 5 percent of the population as being at high risk [for Down syndrome], and that population would go on to have an invasive test. These 5 percent will contain between 90 percent and 95 percent of the babies that have Down syndrome.

With the new test, we can detect more than 99 percent of [Down syndrome], and at the same time, we will not falsely classify 5 percent of the population as being at high risk but only 0.1 percent, and I think actually less.

So it's a major improvement in terms of detection rate and the massive drop in the false positive rate, [thus] avoiding the potential of miscarriage through an invasive test.

[However], I think it's very important to not compare the ultrasound and the blood test with the new cell-free DNA test because I believe those tests most probably will remain. The ultrasound is being done to find out if the woman is indeed as many weeks as she thinks she is, whether she is carrying one baby or more, whether the baby is alive or not, whether it has other major abnormalities beyond Down syndrome, for example of the brain or the heart. So it's not a test in competition with the ultrasound and the biochemical tests but it's supplemental to those.

How did you choose Ariosa's test over that of its competitors, like Sequenom or Verinata?

If you are going to apply a test to a large proportion of your patients, it has to be affordable, and Ariosa's test was by far cheaper − the Harmony test we have been using is being sold at the moment for £400 ($650). We had worked with Ariosa before, but I had also worked closely with Dennis Lo and others.

What's your experience with the test been like so far?

We now have a month and a bit of experience, and we have learned a whole series of things from that.

[We wanted to find out, for example,] how much counseling was necessary and how well patients would accept it, in comparison with traditional methods of testing. And I was overwhelmed by the desire of women, if they could have an answer in relation to Down syndrome and other common chromosomal abnormalities, to avoid having an invasive test.

The second thing was the logistics of collecting samples in London and then having FedEx come and pick them up and ship them to California for analysis. I was afraid there could be logistical problems that could end up producing failures. I was very pleased to find out that it works well, however ridiculous it may sound that samples are collected from London and go to California.

The uptake has been fantastic. We have been getting results with a very low, less than 2 percent, no-result rate. In those cases, we repeated the sample and it worked. We already avoided a lot of unnecessary invasive tests, we already diagnosed five chromosomal abnormalities, and at least one of those I would have missed with the combined [nuchal translucency and biochemical] test.

Do you follow up on a positive test result with an invasive test?

Always. It is essential that you do that, because even if the false-positive rate is 0.1 percent or less, you do not want to have someone think the baby has Down syndrome and it's actually normal.

How does the test currently perform in twin pregnancies?

There is a study using the Sequenom technology in 25 twin pregnancies, where it was shown to work quite well. I know that Ariosa and other companies are developing their tests for twins and very soon, we will begin to see results from these. Twins will not be a group to be excluded from testing.

Is the test an out-of-pocket expense right now, or is it covered by the UK's National Health Service?

At the moment, it is being practiced on a private basis. We are now in the final stages of planning a study where we would use it as a pilot study within the NHS. In addition to having the scientific evidence that something works, you need to demonstrate the logistics of implementation within the NHS, and that is what I intend to do, starting in April.

Besides your own center, how has non-invasive prenatal testing been adopted in the UK?

Ours was the first health center to start testing. I introduced the test almost in a shy way to work out patient acceptability and the logistics of it, and I didn't go out of my way to promote it; I wanted to have this period of assessment.

[In early December], we had a major meeting with more than 800 people from more than 70 countries, and there was enormous interest, and of course the other companies were there and people were talking to all the companies. So I expect that over the next few weeks, we will be seeing a major uptake in not only England but in many other European countries.

How soon do you expect the NHS to offer this test?

I wrote my first paper on nuchal translucency in 1992. I then published the implementation in 100,000 pregnancies in the Lancet in 1998, and the NHS adopted the method in 2004. After 12 years of, in a sense, resistance, they called me and said, 'Please give us a hand, in three months, it must be implemented in all the hospitals in England.' I do not believe that the interval will be so many years this time. I think the major improvement in performance and the pressure that will come from the population will ensure that this happens a lot earlier.

But the first step is to show, even within the private sector, that this works, then to show how it can be implemented within the NHS, and then, hopefully, in the next three years, my expectation is that the NHS as a whole will seek to implement it for the whole country. That will require a lot of health implementation and health cost analyses, and so on.

How do you expect this test to develop further in the future?

I think two major things will happen. In terms of routine screening for the whole population, the cost will be dramatically reduced. And in terms of the scientific element, there will be an expanding number of chromosomal abnormalities that would be diagnosable, and then genetic conditions that now require invasive testing will be amenable to this approach. There is no reason why it would not — it's a matter of further research and logistics rather than any basic scientific principle that would inhibit it.

In countries like Germany, there has been a lively discussion about the ethical implications of early Down syndrome screening, which some have called a "search-and-destroy" operation. In other countries, like the US, this discussion appears to have been almost absent. What is it like in the UK?

Whenever there is any development in screening, there will be certain groups of people who will see this as a search-and-destroy exercise and anti-Down syndrome. I have met with representatives of these groups, and I don't want to underestimate their moral argument.

But for me, the argument is a different one. Within a society, there will be people who believe that Down is not a condition for which we should be screening and terminating, and many others who believe that it is morally acceptable to do so. Irrespective of which moral principles you have, if we screen, it is extremely important that the method of screening that we use performs well, so that you do not produce enormous amounts of anxiety, and you reduce what I call the collateral damage, the false positive rate.

I think that the arguments [for or against screening] will remain forever. Certain groups will see any development as being a good thing or a bad thing. To me, for those who want to have screening, this is a major advance. In Germany, they do have these discussions, obviously, because of [their history of eugenics]. But the truth of the matter is that in Germany, there is an extremely high uptake of the first trimester combined screening test. This would be an addition, an improvement, over what we have for those who have chosen to have screening.