Fetal nuchal translucency scan and early prenatal diagnosis of chromosomal abnormalities by rapid aneuploidy screening: observational study
BMJ 2006; 332 doi: https://doi.org/10.1136/bmj.38730.655197.AE (Published 23 February 2006) Cite this as: BMJ 2006;332:452
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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
Competing interests: No competing interests
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
Competing interests: No competing interests
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
Competing interests: No competing interests