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Optimising prenatal diagnosis of Down's syndrome - full karyotyping contra-indicated for women referred solely for risk of Down's syndrome.
- Caroline Ogilvie, Alison Lashwood, and Frances Flinter (2 March 2006)
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Re: Optimising prenatal diagnosis of Down's syndrome - full karyotyping contra-indicated for women referred solely for risk of Down's syndrome.
- Jim Neilson, Zarko Alfirevic (3 March 2006)
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Risk-free prenatal diagnosis of Down's syndrome
- Maj A Hulten, Maj A Hulten, Ala Szczepura (9 February 2007)
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Caroline Ogilvie, Principal Scientist Guy's & St Thomas NHS Foundation Trust, London SE9 4RQ, Alison Lashwood, and Frances Flinter
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Dear Sirs, 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 QF-PCR plus full karyotyping for fetuses with 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 Genetics Centre, Guy’s & St Thomas’ NHS Foundation Trust, 5th Floor, Guy’s Tower, St Thomas St, London, SE1 9RT, UK. 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: 1369-1375. 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: None declared |
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Jim Neilson, Professor of obstetrics & gynaecology University of Liverpool, Zarko Alfirevic
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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 karyotyping. Competing interests: None declared |
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Maj A Hulten, Professor of Medical Genetics Department of Biological Sciences, University of Warwick, Coventry CV$ 7AL, Maj A Hulten, Ala Szczepura
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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 loss rates. 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 Sciences Ala Szczepura, Professor Health Services Research, Warwick Medical School University of Warwick, Coventry CV4 7AL References 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. DOI:10.1016/S0140-6736(07)60115-9 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 Competing interests: MH is the director of Simeg Ltd and has filed patents on technology for non-invasive prenatal diagnosis |
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