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PAPERS: R E Gilbert, C Augood, R Gupta, A E Ades, S Logan, M Sculpher, J H P van der Meulen, Euan M Wallace, and Sheila Mulvey Screening for Down's syndrome: effects, safety, and cost effectiveness of first and second trimester strategies • Commentary: Results may not be widely applicable • Authors' response BMJ 2001; 323: 423 [Abstract] [Full text]

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Someone should actually perform the tests

Izhar Ben-Shlomo   (25 August 2001)

Screening for Down Syndrome

Martin Whittle   (25 August 2001)

Down Syndrome,a life worth living?

Marga Hogenboom   (25 August 2001)

Screening for Down's syndrome

Kieran Harkin   (28 August 2001)

Antenatal screening; the human costs

Josephine Venn-Treloar   (28 August 2001)

Conclusions do not reflect reality

Tim Reynolds   (28 August 2001)

A caring society.

C O'Loughlin   (29 August 2001)

Re: A caring society. Paternalistic atavism or Medea?.

James S Smeltzer   (31 August 2001)

Life with disability as an economic disbenefit

Alison Davis   (4 September 2001)

Nuchal translucency screening and congenital heart disease.

John Simpson   (10 September 2001)

Modeling does not reflect reality

David Howe   (14 September 2001)

Ultrasonographic Femur-Tebial Length Ratio in Antenatal Screening for Down Syndrome

Jacob M Puliyel   (22 September 2001)

Costs of Down's syndrome screening

David Hill   (23 October 2001)

Someone should actually perform the tests 25 August 2001
Izhar Ben-Shlomo, Visiting Associate Professor Dept. Gyn/Ob, stanford Un. Med. Ctr. Send response to journal: Re: Someone should actually perform the tests	Figures relating to the relative efficiency of various screening modalities for Down's syndrome are comstantly being modified, according to the latest input by studies and the accumulation of all historical data. Every now and then, people with the appropriate tools (such as the program which sponsored Gilbert et al.'s project) come up with newly balanced picture. The usual responses to such publications limit scrutiny to the numbers themselves and their applicability to certain different setting, in other countries for example. Few references are made to the profound effect of decisions, which would rely on these analyses, on the medical infrastructure involved. Moreover, the entailed cost of changing the relative proportions of the involved trained professionals was not highlighted. We remain therefore with the hard-to-answer question: how quickly should health authorities worldwide respond to these analyses, before a new analysis indicates somewhat different delicate balance between projected costs? and how much would too quick responses cost?
Screening for Down Syndrome 25 August 2001
Martin Whittle, Chairman Antenatal Subgroup of National Screening Committee Birmingham Womens Hospital Send response to journal: Re: Screening for Down Syndrome	EDITOR - The paper by Gilbert et al,(1) provides an interesting cost and effectiveness analysis for Down syndrome screening using mathematical modelling. Costing of procedures undertaken in the NHS is notoriously difficult and the authors are to be congratulated on their attempt. In essence they conclude that there are four screening strategies which are cost effective and efficient. Nuchal translucency(NT) screening is apparently the cheapest procedure at £4.4 per test. Unfortunately there is no indication how this figure was derived. In a cost analysis undertaken for ultrasound scanning for the RCOG (2) the cheapest scan in 1995 cost about £35. Of course this figure was probably unreliable but there does seem to be a large discrepancy which is important to resolve since their quoted NT costs are crucial to their model. If the costing is inaccurate then the conclusions of the study are likely to be incorrect. The literature generally agrees that NT together with serum testing seems an efficient screening method something confirmed by this model. However the practical problems which surround implementation of such a programme nationally are formidable. As mentioned in this paper only about 7% of units are offering NT. There are well recognised radiographer shortages and possibly inadequate facilities in some circumstances. Early screening demands effective counselling before the women gets to the hospital so she has time to consider her options. One of the benefits of an early diagnosis is a surgical termination but in this model only about one third of women had their diagnosis in time. Early diagnosis also increases the demand for chorionic villus sampling which is generally available only in fetal medicine centres and in any case carries a higher miscarriage rate than amniocentesis and has higher laboratory costs. Currently about 60% of women in the UK are offered at least a double test. This paper indicates the weakness of that strategy but it is a starting point and the addition of other analytes would not necessarily be difficult. For a variety of reasons second trimester screening is likely to be more feasible to support than first trimester screening, largely because of the difficulties of implementing NT measurements. This model suggests that a quadruple test may prove effective and although there would be an increased cost the test involves automated, laboratory techniques and not those dependent on a skill-based technique such as NT. The challenge is to find a technique which is not only cost effective and safe but one which is also feasible to implement nationally. References 1 Gilbert, R.E.,Augood C.,Gupta R.,Ades A.E.,Logan S.,Sculpher M.,Meulen van der J.H.P. Screening for Down’s syndrome: effects, safety and cost effectiveness of first and second trimester strategies. BMJ 2001; 323; 423-425. 2 Ultrasound Screening for Fetal Abnormalities. Reprt of the RCO
Down Syndrome,a life worth living? 25 August 2001
Marga Hogenboom, Medical Officer Camphill Rudolf Steiner Schools Aberdeen Send response to journal: Re: Down Syndrome,a life worth living?	Down Syndrome, life worth living? The artcle about screening for Down Syndrome rightly tries to establish the most effective way of screening. But there is one aspect I miss in this article and orther articles on screening for Down Syndrome. What is the value of a person with Down Syndrome? I have been the last 20 years in the privileged situation to meet daily people with Down Syndrome, both as a medical officer and sharing my house with different people with this condition. I am realistic regarding the challences a person with this condition and his or her family meets. But my main experience is that my mood brightens after meeting a person with Down Syndrome and this is not an experience I have with every encounter in daily life. Down Syndrome is in my experience a life that is surely worth living and almost all involved families would fully agree with me. Dr Marga Hogenboom Competing interests;none
Screening for Down's syndrome 28 August 2001
Kieran Harkin, General Practitioner Inchicore, Dublin 8 Send response to journal: Re: Screening for Down's syndrome	I am disturbed at the dispassionate approach to antenatal screening of Down's Syndrome. While I acknowledge that attitudes to abortion vary enormously, surely we all agree that the the foetus with Down's Syndrome has some rights and I suggest these merit mention , even if the paper is on cost effectiveness.
Antenatal screening; the human costs 28 August 2001
Josephine Venn-Treloar, GP assistant Welling Send response to journal: Re: Antenatal screening; the human costs	Dear Sir In their study Gilbert et al [ref 1] made no provision for the cost of counselling. I still hear from women who go for antenatal care and find they are screened without consent or counselling [see ref 2 for background]. Some of these women regret entering a conveyor belt process which ends up with an invasive procedure which causes a high rate of fetal loss. The paper, by highlighting the economic implications of screening, only serves to remind us that mothers and their unborn babies continue to be used in what is primarily a cost saving procedure. Doubt has already been cast upon the public health benefits of screening and the ethical component of such programs [ref 3]. No pregnancy is replaceable. The cost of the screening in human terms has not been evaluated. By excluding the costs of counselling and disregarding mothers’ rights and the worth and value to society of children with Down’s syndrome, Gilbert et al study, has severe limitations which should prevent us from embracing such screening strategies. 1) gilbert et al. BMJ 2001; 323: 423-425 2)J Venn-Treloar . Nuchal Translucency- Screening without consent BMJ1998;316:1026 3)C Ford. The value of screening for Down’s Syndrome in a socio- economically deprived area with a high ethnic population. Brit J Obs Gynae 1998; 105: 855-859
Conclusions do not reflect reality 28 August 2001
Tim Reynolds, Consultant Chemical Pathologist Queen's Hospital, Burton-on-Trent Send response to journal: Re: Conclusions do not reflect reality	Sir, Gilbert et al, have made a valiant attempt to identify the best approach for Down’s syndrome screening (1). Sadly, they have fallen into the trap of uncritically evaluating the published literature. There is in fact no statistical proof that the detection rate is significantly better for any of: triple screening versus double screening; quadruple screening vs. double or triple screening; first trimester screening versus second trimester screening; or that the integrated test is an improvement (2). All studies of Down syndrome screening have had relatively small numbers of examples of Down’s positive pregnancies. Consequently, although false positive rates can be accurately assessed, the detection rate cannot. The confidence intervals about the detection rate are so wide that no one has yet proved that superiority of one method over another is not entirely due to chance (2). It has also been known for a long time that where small numbers have been used to derive a ‘population model’ which is used to estimate false positive and detection rates, large errors can result from an error in the estimate of the population variance for a single analyte giving rise to a hopelessly optimistic estimate of the effectiveness of a procedure (3). Studies of the efficacy of nuchal translucency screening have all been interventional and therefore the quoted detection rate (of the order of 80%), needs to be deflated to account for natural fetal losses. The effect of natural fetal loss is to reduce the detection rate for first trimester screening to less than 60%, making it comparable to second trimester screening (4). In addition, for nuchal translucency measurement, there is a far greater incidence of failure to be able to make a measurement than there is failure of biochemical testing to be able to produce a result, which further depresses the detection rate. Finally, there are serious statistical doubts about the integrated test, as well as worries about the ethics of withholding early positive results until a second test (5). The unit costs estimated for the different tests are also interesting. How can it be that an ultrasound test requiring 15-20 minutes of hands-on technical work is cheaper than a biochemical test, when one person can analyse 100’s of samples per day. Since the detection rates for nuchal translucency are grossly over estimated and the integrated test is expensive and unproven, the conclusion that these two modalities of screening represent the cost- effectiveness boundary cannot be left unchallenged. REFERENCES 1) Gilbert RE, Augood C, Gupta R, Ades AE, Logan S, Sculpher M, van der Meulen JHP. Screening for Down’s syndrome: effects, safety, and cost effectiveness of first and second trimester strategies. BMJ 2001; 323: 423 -5 2) Reynolds TM. Downs syndrome screening: A controversial test with more controversy to come! J Clin Path: 2000; 53: 893-8 3) Reynolds TM. Chapter 4: Screening by test combination: a statistical overview. pp47 – 71. IN: Screening for Down’s syndrome. EDS: Grudzinskas JG, Chard T, Chapman M, Cuckle H. University Press, Cambridge. 1994. 4) Reynolds T.Antenatal Screening for Down’s Syndrome. Lancet 1998: 352; 1145 5) Reynolds T, Zimmermann R, Wright E. Integrated Screening for Down's Syndrome. NEJM 1999: 341; 1395-7
A caring society. 29 August 2001
C O'Loughlin, Psychiatry SHO Bury St. Edmunds Send response to journal: Re: A caring society.	Dear Sir, I would like to say how proud I feel to be living in a society that seeks out the cheapest way to destroy an unborn child with Down's syndrome (1), and particularly how glad I am that efforts are made so that no-one should 'slip through the net' - with "the main considerations for providers of screening for Down's syndrome should be minimising the risk of babies with Down's syndrome being missed by the test..." (1) Yours sincerely, Dr. C. O'Loughlin Psychiatry (1) Screening for Down's syndrome: effects, safety, and cost effectiveness of first and second trimester strategies, RE Gilbert et al., BMJ 2001;323:423 ( 25 August )
Re: A caring society. Paternalistic atavism or Medea?. 31 August 2001
James S Smeltzer, Consultant, Maternal Fetal Medicine Wellstar Physicians' Group Send response to journal: Re: Re: A caring society. Paternalistic atavism or Medea?.	Implicit in the discussions of the high cost of counselling, the original article and many of the letters of response, including the current sarcastic one, are the crass and paternalistic assumptions that the only "benefit" of identification of fetuses with Down Syndrome is abortion, or that our poor confused women patients are better off if they have no opportunity to deal with inherently difficult possibilities and diagnoses. These are both hogwash. As a pro-life perinatologist I have had many opportunities to see the joy that infants with Down Syndrome and other special problems bring to families who are prepared to receive them. Thanks mostly to the excellent help of the sonographers I work with, we have been able to help almost all of the families so affected to either prepare for this event, avail themselves of special needs adoption or choose abortion when it is the only option they can take. I have also helped families who were surprised by such arrivals. I can say with absolute certainty that knowledge and the opportunity to separate the bad news in time from the blessed event, and prepare for it is better for the woman and her family in almost all cases. Overlapping the three life-defining events of birth, death and reproduction produces a tidal wave that can founder good families and inflict permanent psychological damage on parents, siblings and the affected child. Regardless of the circumstances, the opportunity for us to intervene with our honest care and support in such a crisis gives us each a chance to act as the instrument of God's love David talks about in the 23rd Psalm, and Jesus talks about in the Sermon on the Mount, which is what entering our profession was all about for us in the first place. Although efficiency is not really the main issue here, our practical experience validates the authors' model and conclusions. We have not yet had a single patient for whom serum testing has correctly predicted Down syndrome in the face of a negative sonogram, and age and serum testing, rather than sonography, have been the source of the large majority of our negative - and thus unnecessary - amniocenteses. Training sonographers is not easy, but its reward of accurate identification of antenatal and gynecologic problems easily justifies the trouble it takes. All data I have seen so far indicates that this training in the UK is far better, in general, as measured by published accuracy of results and correct identification of problems, than on this side of the Atlantic. Whatever you have been doing, please keep it up, and use this resource! It is not only more cost-effective, it gives better results. It also opens up the family to the secret of the life within in a way that is not otherwise possible, which is an inherently good thing to do.
Life with disability as an economic disbenefit 4 September 2001
Alison Davis, National Coordinator, Handicap Division of the Society for the Protection of Unborn Children Dorset Send response to journal: Re: Life with disability as an economic disbenefit	Dear Sir, The article by Gilbert et al makes profoundly depressing reading for people with disabilities and those who share our view that disability does not affect the value, dignity and status of the individual who has it. This study draws the conclusion that our country benefits to the tune of £22,000 for each baby with Down's Syndrome who is detected by pre-natal screening and killed by abortion. In making this callous calculation the authors do not consider at all the contribution a disabled person makes to their family and to society in general, nor the effects of reading such eugenic statements on a minority group. In an age where discrimination against minorities is normally regarded as universally unacceptable, it is sad that fatal discrimination is discussed and considered appropriate by doctors. I owe my life to doctors, yet now members of the same profession would quite happily kill an unborn child on the grounds that s/he would grow up to be like me. I have myelomeningocele spina bifida,and the additional conditions of emphysema and osteoporosis. The SPUC Handicap Division has over 300 disabled members, including many with Down's Syndrome who are outraged at this latest assault upon their human dignity and worth. I suggest that doctors, including Gilbert et al, should be reconsidering their attitude towards "detectable" disability. Are people like me really so undesirable that our existence is an economic disbenefit to the world? If so, why continue to allow us to live, even if "wanted" by our parents. If not, why continue this search and destroy policy which is a denial of our most fundamental human right - the right to life itself. Yours faithfully, Alison Davis
Nuchal translucency screening and congenital heart disease. 10 September 2001
John Simpson, Consultant in Fetal and Paediatric Cardiology Guy's and St Thomas' Hospitals, London, UK Send response to journal: Re: Nuchal translucency screening and congenital heart disease.	Screening for Down’s syndrome during fetal life has received much attention with over 350 articles in the medical literature over the past five years alone. The cost effectiveness data of Gilbert et al (1) is welcome given the variable screening strategies offered by different NHS providers. Increased nuchal translucency may be a marker of many fetal diseases (2) and a discussion of its cost effectiveness should not be restricted to Down’s syndrome alone. Congenital heart disease (CHD) is the most common type of fetal malformation (at least 8/1000 during fetal life), but only 25% of significant malformations are actually detected prenatally in the UK (3), which is worse than any other type of fetal anomaly. Increased nuchal translucency is associated with CHD, independent of karyotypic abnormalities, with a sensitivity of 15 – 56%(4,5,6). Although far from perfect as a screening tool for CHD, nuchal scanning makes some contribution to prenatal detection of CHD as well as its value in detecting chromosomal abnormalities. This is highly relevant when the relative merits and cost effectiveness of prenatal screening strategies are evaluated. 1. Gilbert RE, Augood C, Gupta R, Ades AE, Logan S, Sculpher M, van der Meulen JHP. Screening for Down’s syndrome: effects, safety, and cost effectiveness of first and second trimester strategies. BMJ 2001;423 – 425. 2. Souka, A P, Krampl E, Bakalis S, Heath V, Nicolaides K. H. Outcome of pregnancy in chromosomally normal fetuses with increased nuchal translucency in the first trimester.Ultrasound Obstet Gynecol 2001;18: 9- 17. 3. Bull C. Current and potential impact of fetal diagnosis on prevalence and spectrum of serious congenital heart disease at term in the UK. British Paediatric Cardiac Association. Lancet 1999;354:1242-7. 4. Mavrides E, Cobian-Sanchez F, Tekay A, Moscoso G, Campbell S, Thilaganathan B, Carvalho JS. Limitations of using first-trimester nuchal translucency measurement in routine screening for major congenital heart defects Ultrasound Obstet Gynecol 2001; 17 : 106 – 110. 5. Michailidis GD, Economides DL. Nuchal translucency measurement and pregnancy outcome in karyotypically normal fetuses. Ultrasound Obstet Gynecol 2001 ; 17 : 102-105. 6. Hyett J, Perdu M, Sharland G, Snijders R, Nicolaides KH. Using fetal nuchal translucency to screen for major congenital defects at 10–14 weeks of gestation: population based cohort study. BMJ 1999; 318: 81–5
Modeling does not reflect reality 14 September 2001
David Howe, Consultant in feto-maternal medicine Wessex Fetal Medicine Unit, Princess Anne Hospital, Southampton Send response to journal: Re: Modeling does not reflect reality	Editor, On the basis of their analysis of antenatal screening strategies for Down syndrome, Gilbert and colleagues state without qualification that “the integrated test is the most effective and safest strategy. All other strategies result in more liveborn babies or miscarriages of unaffected pregnancies.” It is difficult to think of any other area of medicine where decisions about health policy affecting a large section of the population are driven so much by mathematical modelling rather than properly gathered clinical evidence. Any engineer who relies on modelling is aware that there may be wide differences between the model and real life unless both the model and the underlying assumptions are correct. As a profession we lose scientific credibility by continuing to allow screening policy to be driven by modeling without evidence from controlled trials that confirm that the presumed benefits of the various policies are achieved in practice. The benefits of the integrated test are all assumed from modelling since the test has never been tested, even in a large uncontrolled demonstration project. There is, however, clear evidence that modelling does not accurately predict the true effectiveness of screening programmes in practice. We demonstrated last year (1) that a policy based on maternal age used in Southampton, a unit where routine anomaly scanning was offered, was much more effective than predicted, detecting 68% of cases antenatally over a six year period. In a demonstration project of serum screening using the double test from the West Midlands (2) only 6 of 19 cases of Down syndrome were diagnosed antenatally (31%). The modelling used present study presumes that in Southampton study the detection rate should have been 32% and in the West Midlands 60%. Why are there such differences between modelling and reality? Firstly, because, quite rightly, pregnant women do not act as they are expected to by those offering screening. In Southampton 7 of the 17 mothers who had children with postnatally-diagnosed Down syndrome had been offered, but declined, antenatal testing. In the West Midlands the uptake of serum screening was only 71%, so only 13 of 19 cases occurred in women who had undergone screening. Only 11 of these 13 women had positive screening, and only 6 of the 11 women with positive tests opted for invasive testing. In the 6 antenatally-diagnosed pregnancies with Down’s only 4 mothers chose to terminate their pregnancies. At every point women made choices that differed from those presumed in the mathematical modelling. In other screening programmes women make choices in the opposite direction. Many older mothers in areas offering biochemical or nuchal translucency screening decline these in favour of the definitive diagnosis achieved from an invasive test: they are unwilling to take any risk of having an affected child, however low screening suggests it to be, and this increases the amniocentesis rate above that predicted from modelling. A second reason for the discrepancy between modelling and reality is the change in the age structure of the antenatal population. Modelling assumes that 5% of pregnant women are aged over 35 whereas in much of the UK this proportion is much higher. In Southampton it is over 10% resulting in over 65% of cases of Down’s arising in this group of older women(1). Finally, Gilbert’s study makes no attempt to consider the impact of screening on pregnant mothers, assuming as it does that screening is only a positive benefit. Universal screening polices, especially those used early in pregnancy, must be discussed with all mothers at a very early stage and pregnant women increasingly feel and complain that midwives and doctors are not interested in their pregnancies until they have ruled out the possibility of Down syndrome. This is not a message we can be proud of. An age-based policy need only be discussed with a small segment of the population, who are often aware of the higher risk of Down’s when planning their pregnancy and have already considered the possibility of testing. The data from the two studies I have quoted clearly demonstrate that whilst modelling may indicate that screening strategies are worthy of study, the choice of the best screening policy should only be made on the basis evidence from controlled clinical trials. 1. Howe DT, Gornall R, Wellesley D, Boyle T, Barber J. Six year survey of screening for Down's syndrome by maternal age and mid-trimester ultrasound scans. British Medical Journal 2000;320:606-10. 2. Ford C, Moore AJ, Jordan PA, Bartlett WA, Wyldes MP, Jones AF, et al. The value of screening for Down's syndrome in a socioeconomically deprived area with a high ethnic population [see comments]. British Journal of Obstetrics & Gynaecology 1998;105(8):855-9.
Ultrasonographic Femur-Tebial Length Ratio in Antenatal Screening for Down Syndrome 22 September 2001
Jacob M Puliyel, Consultant Pediatrician St Stephens Hospital, Tis Hazari, Delhi 110054 India Send response to journal: Re: Ultrasonographic Femur-Tebial Length Ratio in Antenatal Screening for Down Syndrome	Ultrasonographic femur - tibial length ratio in antenatal screening for Down's Syndrome. Sir, We refer to the article by Gilbert et al (1) and a previous paper by Howe et al(2) which rely heavily on maternal age to screen for Down Syndrome. However, maternal age is not so useful in India and other countries where early marriage is the norm and there are enormous social pressures for early motherhood. In our series which included 3000 deliveries and 7 babies with DS, we saw that all babies with DS were born to mothers under 35 years of age. In the recent issue of the American Journal of Perinatology (3) we report our finding that the ratio of Femoral Length to Tibial Length remains remarkably constant around 1.15(range 1.13 - 1.19) in fetuses after 13 weeks of gestation. Fetuses with DS had this ratio greater than 1.2 with SD score of 4.5 when compared to norms. The youngest fetus with DS in our sample was 22 weeks at the time of measuring. We hope that this ratio will be evaluated more extensively and earlier in pregnancy, to see if these findings are valid in the early second trimester and across ethnic groups. Pooja Sachdev Shubhra Bahl Jacob M. Puliyel Department of Pediatrics, St. Stephen's Hospital, Delhi email-puliyel@vsnl.com References (1) R E Gilbert, C Augood, R Gupta, A E Ades, S Logan, M Sculpher, J H P van der Meulen, Euan M Wallace, and Sheila. Screening for Down's Syndrome: effects,safety and cost effectiveness of first and second trimester strategies. BMJ 2001; 323:423-425. (2) Howe DT, Gornall R, Wellesley D, Boyle T, Barber J. Six years survey of screening for Down's Syndrome by maternal age and mid trimester ultrasound scans. BMJ 2000 ; 320:606-610 (3) Gupta R, Thomas RD, Sreenivas V, Walter S, Puliyel JM. Ultrasonographic Femur-Tibial Length Ratio: A Marker of Down Syndrome from the late second trimester. American Journal of Perinatology,2001; 18 : 217 -223.
Costs of Down's syndrome screening 23 October 2001
David Hill, General practitioner Oxted Send response to journal: Re: Costs of Down's syndrome screening	The costs of ultrasound scanning are surely to be included for all tests as serum screening needs proper dating to achieve the high level of accuracy suggested. In the experience of our centre, extra time taken by a trained, experienced sonographer to perform a nuchal tranlucency in addition to an early fetal anomaly screen is negliglible. It is important for all women to have an early scan for dating accurately, determining chorionicity of twins, excluding major fetal defects such as anencephaly and the 3% of women who will have a failed early pregnancy.The issue of fully trained sonographers is paramount to the success of all screening and this should be one of the main goals of prenatal screening. The NSC are awaiting the results of the SURUSS study but I am concerned that even in this trial, if sonographers are inadequately trained, this will have a substantial effect on results. I was suprised that Professor Nicolaides has apparently not been involved in the study - either in implementation or in quality assurance