Optimising prenatal diagnosis of Down's syndromeBMJ 2006; 332 doi: https://doi.org/10.1136/bmj.332.7539.433 (Published 23 February 2006) Cite this as: BMJ 2006;332:433
All rapid responses
Following an editorial in the BMJ on optimising prenatal diagnosis of
Down’s syndrome (1), a recent report by Dhallan et al (2) on the potential
for risk-free prenatal diagnosis of Down’s syndrome (DS) by the use of
maternal blood samples alone has attracted much media attention. There
have also recently been a number of other reports (3,4) indicating that
this might soon become a viable alternative to current prenatal diagnosis,
where unfortunately amniocentesis and chorionic villus sampling (CVS) are
associated with a fetal loss rate of around 0.5-1%.
The outstanding question is then how best to introduce such new non-
invasive prenatal diagnosis (NIPD) for DS in relation to currently
available maternal DS screening programmes. These schemes include in
particular serum screening and ultrasound for fetal nuchal translucency
(NT). Might the best option be to adopt NIPD as an adjunct to current
screening tests? Or would it make more sense to introduce NIPD as a
replacement for the NT part of the screening, which is the most expensive
and labour intensive? Or indeed, would the best solution be to simply
replace current screening with the new NIPD test? Many people seem to a
priori find this latter option the most logical.
The situation in the UK as regards maternal DS screening is quite
different to that in many other countries. On the one hand the first
trimester screening facilities and the one-stop-clinics in London are the
most advanced world wide. In this clinical setting, the sensitivity of
screening for DS is 92.6% and the specificity 94.8% (5). Yet again, many
Obstetric Units up and down the country still rely on either second
trimester screening alone or a combination of first and second trimester
screening with much lower detection rates.
It is obvious that the best way forward will require consideration of
the economic as well as social implications of NIPD. We would argue
therefore that there is now no time to lose in looking at these. This
notion is of special importance considering the potentially very high
uptake by pregnant women of a new risk-free diagnostic test compared to
current schemes requiring CVS or amniocentesis, with their inherent fetal
Any policy for introducing a new non-invasive prenatal DS diagnosis
programme is likely to become the responsibility of the UK National
Screening Committee (6). We hope that a timely and careful analysis by
researchers of the options, along with supporting evidence and an
effective national planning strategy, will assist in providing a coherent
and clear policy for the future. The continued debate around existing
screening and diagnostic DS tests, including molecular ones, should
hopefully dissipate with the obvious advantages that these new
developments can bring.
Maj Hultén, Professor Medical Genetics, Department of Biological
Ala Szczepura, Professor Health Services Research, Warwick Medical School
University of Warwick, Coventry CV4 7AL
1. Editorial: James P Neilson and Zarko Alfirevic. Optimising prenatal
diagnosis of Down's syndrome. BMJ 2006; 332: 433-434
2. Dhallan R, Guo X, Emche S, Damewood M, Bayliss P, Cronin M, Barry
J, Betz J, Franz K, Gold K, Vallecillo B, Varney J. A non-invasive test
for prenatal diagnosis based on fetal DNA present in maternal blood: a
preliminary study. Lancet. Published Online February 2, 2007.
3. Lo YM Fetal DNA in maternal plasma: progress through epigenetics.
Ann N Y Acad Sci. 2006 Sep;1075:74-80
4. Lo YM, Tsui NB, Chiu RW, Lau TK, Leung TN, Heung MM, Gerovassili
A, Jin Y, Nicolaides KH, Cantor CR, Ding C. Plasma placental RNA allelic
ratio permits noninvasive prenatal chromosomal aneuploidy detection. Nat
Med. 2007 Jan 7; [Epub ahead of print]
5. Nicolaides KH et al. Multicenter study of first-trimester
screening for trisomy 21 in 75 821 pregnancies: results and estimation of
the potential impact of individual risk-orientated two-stage first-
trimester screening. Ultrasound Obstet Gynecol. 2005 Mar;25(3):221-6.
6. National Screening Committee (www.screening.nhs.uk/downs/home.htm)
Conflicts of interest
MH is the Director of Simeg Ltd and has filed patents on NIPD technology
MH is the director of Simeg Ltd and has filed patents on technology for non-invasive prenatal diagnosis
Competing interests: No competing interests
Re: Optimising prenatal diagnosis of Down's syndrome - full karyotyping contra-indicated for women referred solely for risk of Down's syndrome.
Caroline Ogilvie and colleagues are absolutely correct that the
sentence in our editorial about picking up 'more truly positive cases of
Down's syndrome' makes no sense. It was a post-proof change by BMJ
editorial staff, and we have already asked the BMJ to insert a note of
correction about this mistake. Ogilvie et al are probably also correct in
saying that if qf-PCR had been available during the 1960s, full
karyotyping would not have become the standard laboratory investigation
after amniocentesis or chorion villus sampling. It is also true that more
information is not always better (consider ultrasound detection of fetal
choroid plexus cysts) but we do strongly believe that pregnant women are
entitled to make (and capable of making) rational and informed decisions
about prenatal screening tests, invasive testing and, potentially, full
Competing interests: No competing interests
Optimising prenatal diagnosis of Down's syndrome - full karyotyping contra-indicated for women referred solely for risk of Down's syndrome.
We welcome the paper by Chitty et al (1), which proposes a strategy
for Down syndrome detection based on QF-PCR testing alone for fetuses with
NT<_4mm and="and" qf-pcr="qf-pcr" plus="plus" full="full" karyotyping="karyotyping" for="for" fetuses="fetuses" with="with" nt="nt"/>4mm.
This is in line with the recommendations put forward in our publication
last year (2) following a London-wide audit of chromosome abnormalities in
patients referred for increased risk of Down’s syndrome.
The commentary by Professors Neilson and Alfirevic (3), however,
contains some errors and omissions that we would like to address. They
state that full karyotyping will pick up “more truly positive cases of
Down's syndrome”. In fact, QF-PCR will detect all true cases of Down’s
syndrome; other chromosome abnormalities that may be detected by full
karyotype analysis are not ‘truly positive cases of Down’s syndrome’, but
incidental findings. Many of these findings will be of unknown clinical
significance. In the above paper on this subject (2), we suggest that
full karyotype analysis, when the referral is for raised risk of Down’s
syndrome, is actually contra-indicated, so this is not simply an economic
argument. The WHO guidelines on screening tests state that these should
have a specified aim and a clear treatment pathway (4). Many of the
unexpected karyotype abnormalities detected by full karyotyping will not
have clear treatment pathways, as their clinical significance is unknown.
Much parental anxiety is generated by the discovery of these chromosome
abnormalities, and pregnancies that are most likely to result in a normal
phenotype may be terminated unnecessarily.
The suggestion made by Professors Neilson and Alfirevic that patients
could be counselled prior to choosing whether or not to have full
karyotype testing is unrealistic, when the professionals themselves do not
understand the significance of the test. The authors have assumed that
more information is always better, but this is not always true if some of
the additional information is of uncertain value or cannot be interpreted.
The reality is that, had the technology been available in the late
sixties, targeted testing for Down’s syndrome by QF-PCR would have been
the gold standard test for those at risk of Down’s. However, full
karyotyping was the only available option then; the time has now come to
recognize it as inappropriate for these patients, and to withdraw testing
from the NHS. This is not only for economic reasons, but also in the
interests of good clinical practice.
Caroline Ogilvie, Principal Scientist
Alison Lashwood, Consultant Genetic Counsellor
Frances Flinter, Consultant Clinical Geneticist; Clinical Director,
Women’s and Children’s Services
Guy’s & St Thomas’ NHS Foundation Trust, 5th Floor, Guy’s Tower, St Thomas St,
London, SE1 9RT,
1. Chitty LS, Kagan KO, Molina FS, Waters JJ, Nicolaides KH. Fetal
nuchal translucency scan and early diagnosis of chromosomal abnormalities
by rapid aneuploidy screening: observational study. BMJ (2006);332: 452-4.
2. Mackie Ogilvie C, Lashwood A, Chitty L, Waters JJ, Scriven PN,
Flinter F. The future of prenatal diagnosis: rapid testing or full
karyotype? An audit of chromosome abnormalities and pregnancy outcomes for
women referred for Down's Syndrome testing.
BJOG: An International Journal of Obstetrics & Gynaecology (2005) 112:
3. Neilson JP, Alfirevic Z. Optimising prenatal diagnosis of Down's
syndrome. BMJ (2006);332:433-434.
4. Wilson J, Jungner G. Principles and Practice of Screening for
Disease. Geneva: World Health Organization; 1968.
Competing interests: No competing interests