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RESEARCH: Lyn S Chitty, Karl O Kagan, Francisca S Molina, Jonathan J Waters, and Kypros H Nicolaides Fetal nuchal translucency scan and early prenatal diagnosis of chromosomal abnormalities by rapid aneuploidy screening: observational study BMJ 2006; 0: bmj.38730.655197.AEv1 [Abstract]

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The other side of the equation in prenatal testing

Edwin P Kirk   (24 February 2006)

The Post-Natal Economic Burden of Limited Karyotyping

Suneel B. Bhat, Sanjay B. Bhat, Jessica Stevens   (27 February 2006)

Is Karytyping Worthwhile?

Ala K Szczepura, Maj Hultén   (14 March 2006)

The other side of the equation in prenatal testing 24 February 2006
Edwin P Kirk, Staff Specialist Dept of Medical Genetics, Sydney Children's Hospital, Randwick NSW 2031, Australia Send response to journal: Re: The other side of the equation in prenatal testing	Chitty et al make a persuasive case that the use of qf-PCR plus selective karyotyping would greatly reduce the costs of prenatal testing for chromosomal disorders. But an important consideration has been left out: the costs of caring for the children missed by this strategy. It is reasonable to assume that about half of the 18 children with important chromosomal abnormalities missed by the suggested combined strategy would survive to birth, with the remaining 9 pregnancies resulting in spontaneous pregnancy loss, or termination following detection of an abnormality on ultrasound. If this is correct, the strategy would only be cost-effective if the average cost to the health care system of caring for these children for their whole lives is less than £180,000 (a ninth of the estimated savings). Since most such children are likely to have major disabilities, this looks to be a very low sum. Savings on the cost of testing are thus likely to be completely wiped out by the cost of caring for the children missed by this approach. Competing interests: None declared
The Post-Natal Economic Burden of Limited Karyotyping 27 February 2006
Suneel B. Bhat, Pre-medical Student Princeton University, Princeton, NJ 08544 USA, Sanjay B. Bhat, Jessica Stevens Send response to journal: Re: The Post-Natal Economic Burden of Limited Karyotyping	Chitty et al. suggest a strategy to identify chromosomal abnormalities that relies on quantitative fluorescent polymerase chain reaction (qf-PCR) and full karyotyping only in cases of fetal nuchal translucency (NT) thickness > 4 mm, as opposed to full karyotyping of all chorionic villous samples.[1] Eliminating double testing results in an upfront economic savings approximately £1.5 million distributed across 17,479 pregnancies. However, such an approach has a failure rate of 1%, the economic consequences of which Chitty et al. neglect to appreciate in their discussion. The incremental lifetime economic costs incurred by an infant born with trisomy 21 is approximately £350,000 (adjusted for 2006 currency).[2] Considering only chromosomally abnormal babies that came to term as well as were undetected by limited karyotyping, and a reasonable termination rate of 70%, the six babies that would have been missed in the study alone represent an economic cost of £2.1 million. Assuming 640,000 yearly births in England and Wales,[3] and necessity for CVS in about 6% of pregnancies,[4] we estimate that a shift from full karyotyping to the approach suggested by Chitty et al. will result in a systemic economic loss of over £5.3 million (i.e. incremental costs of infants born with trisomy 21 – savings from limited karyotyping) each year. This is not to ignore the externalities and intangible costs that may be brought about by missed chromosomal abnormality cases. It may be worth shouldering upfront testing costs in order to provide truly accurate information to mothers, and avoid much greater subsequent societal economic burden. Suneel B. Bhat, Pre-medical Student; Sanjay B. Bhat, Collaborator; Princeton University Jessica Stevens MD, MPH, Chief Pediatric Resident; University of Medicine and Dentistry of New Jersey [1] Chitty L, Kagan K, Molina F, Waters J, Nicolaides K. Fetal nuchal translucency scan and early prenatal diagnosis of chromosomal abnormalities by rapid aneuploidy screening: observational study. BMJ 2006;332:452-455. (25 February.) [2] CDC. Economic costs of birth defects and cerebral palsy-United States, 1992. MMWR 1995;44:694-699. [3] National Statistics. Birth Statistics 2004. Series FM1 no. 33. (accessed on February 24th 2006, at http://www.statistics.gov.uk/downloads/theme_population/FM1_33/FM1_33.pdf) [4] Smith-Bindman R, Chu P, Bacchetti P, Waters J, Mutton D, Alberman E. Prenatal screening for Down syndrome in England and Wales and population-based birth outcomes. Am J Obstet Gynecol 2003;189:980-985. Competing interests: None declared
Is Karytyping Worthwhile? 14 March 2006
Ala K Szczepura, Professor of Health Services Research Warwick Medical School, University of Warwick, Coventry CV4 7AL, Maj Hultén Send response to journal: Re: Is Karytyping Worthwhile?	Will a policy of rapid PCR testing of all CVS samples, with karyotyping only in selective cases (i.e. NT thickness > 4 mm), really ‘reduce economic costs’ as suggested by Chitty et al? [1] We would argue, for the following reasons, that karyotyping remains worthwhile. First, our 2003 HTA report is referenced to support the cost analysis presented, but our wider economic findings are not considered. [2] In terms of economic or cost-effectiveness findings, our HTA trial demonstrated that the use of rapid PCR tests (for trisomy 13, 18, 21, X and Y) plus karyotyping for all women may be acceptable under certain conditions. Based solely on reduced maternal distress associated with more rapid results, and a laboratory with a 1,000 p.a. throughput (UK median 1,200), the cost per quality adjusted life year (QALY) was estimated at £26,514. However, with a 5,000 p.a. throughput, this ratio falls to £13,536 per QALY (£10,520 per QALY, once PCR royalty payments cease). These values are within limits acceptable to bodies such as NICE. [3] Second, it is important to note that the conclusion by Chitty et al is based on monetary costs alone; and even this conclusion may be unfounded. Taking a conservative estimate of 1 clinically significant case remaining undetected per 1,000 samples [1, 4], and the reported annual cost for 5,000 PCR tests (£732,732), the strategy proposed will only make financial sense if the life time cost of caring for a child with mental or physical disability born as a result of this policy is less than £146,500. This is unlikely to be true [5, 6] and, of course, such an analysis does not include the psychological cost to parents or the impact on family life. We would suggest that, before such a policy is considered for widespread implementation, a more detailed appraisal would be required. In particular, the extra cost of measuring fetal NT thickness for all women, as well as the skills required and their availability in local hospitals, would need to be considered by policy makers. Third, the point made by Neilsen and Alfirevic in their Editorial [7] is important to include in any appraisal - "that they [i.e. women] may have to be persuaded that, having gone though an invasive test with 1% miscarriage rate, they should accept a limited analysis because karyotyping is too expensive". In conclusion, we would emphasise that a decision made on test costs, rather than economic grounds, is likely to be misleading. Also, we would suggest that an early health technology assessment should consider quality of life and broader ‘ethical’ implications, such as the ones noted above. We are currently involved in the SAFE Network of Excellence, funded by the EC, which aims to develop and implement non-invasive, prenatal diagnostic tests based on fetal material in maternal blood. [8] If successful, this may help to resolve the increasingly difficult dilemmas facing policy makers in this area. Ala Szczepura, Professor Health Services Research, Warwick Medical School Maj Hultén, Professor Medical Genetics, Department of Biological Sciences University of Warwick, Coventry CV4 7AL 1. Chitty LS, Kagan KO, Molina FS, Waters JJ, Nicolaides KH. Fetal nuchal translucency scan and early prenatal diagnosis of chromosomal abnormalities by rapid aneuploidy screening: observational study. BMJ 2006;332;452-454. 2. Grimshaw GM, Szczepura A, Hultén M, MacDonald F, Nevin NC, Sutton F, et al. Evaluation of molecular tests for prenatal diagnosis of chromosome abnormalities. Health Technol Assess 2003;7(10):1-146. 3. Towse A, Pritchard C, Devlin N. Cost-effectiveness thresholds. OHE / Kings Fund. 2002. 4. Caine A, Maltby AE, Parkin CA, Waters JJ, Crolla JA for the UK Association of Clinical Cytogeneticists, Prenatal detection of Down’s syndrome by rapid aneuploidy testing for chromosomes 13, 18, band 21 by FISH or PCR without a full karyotype: a cytogenetic risk assessment. Lancet 2005;366:123-8. 5. Waitzman NJ, Romano PS, Scheffler RM. Estimates of the Economic Costs of Birth Defects. Inquiry 1994;33:188-205. 6. Petrou S, Sach T, Davidson L. The long-term costs of preterm birth and low birth weight: results of a systematic review. Child: Care, Health & Development 2001;27:97-115. 7. Neilson JP, Alfirevic. Optimising prenatal diagnosis of Down’s syndrome. BMJ 2006;332:433-434. 8. Hultén MA, Szczepura A. The SAFE Network of Excellence. Annals of New York Academy of Sciences, 2006 (in press June 2006) Competing interests: None declared