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Universal Fetal Genotyping of RHD Negative Pregnancies– How Cost-Effective?
- Ala Szczepura, Gouke Bonsel, Christian Krauth, Leeza Osipenko, Alexander Haverkamp (17 April 2008)
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Universal Fetal RHD Genotyping of RhD-negative Pregnancies – How Cost Effective?
- Geoff Daniels, Kirstin Finning, Pete Martin, Joanna Summers, Edwin Massey, Geoff Poole (27 April 2008)
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Ala Szczepura, Professor of Health Services Research Clinical Sciences Research Institute, Warwick Medical School, University of Warwick, Coventry CV4 7A, Gouke Bonsel, Christian Krauth, Leeza Osipenko, Alexander Haverkamp
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The recent article by Finning et al1 provides evidence that non- invasive detection of fetal RHD status can be performed in a high throughput laboratory with high test sensitivity. The associated editorial by Kumar2 suggests that universal fetal genotyping of all RHD negative women is now a logical extension, providing the opportunity to target routine antenatal anti-D prophylaxis (RAADP). This is the main message which has been picked up in press reports3. However, an unanswered question which must be addressed now is whether introduction of such mass testing will be cost-effective and, if so, under what conditions. The original NICE guidance on RAADP introduction in the UK4 was based on a detailed economic analysis by Chilcott et al5. This guidance is currently being reviewed, but the introduction of non-invasive prenatal diagnosis (NIPD) has not yet been specifically addressed. We represent the socio-economic group of the SAFE Network of Excellence6 funded by the European Commission to inform the implementation of a range of NIPD tests. Our group has been exploring the issue of fetal RHD genotyping at the level of various national RAADP programmes, using international NIPD test accuracy data7 and cost comparisons, with sensitivity analyses on pivotal price components. We would caution that, unlike previous developments in the care of RHD negative women i.e. introduction of post-delivery anti-D prophylaxis based on cord blood testing, antenatal prophylaxis for ‘high risk’ events such as spontaneous miscarriage and amniocentesis/ CVS, and most recently routine antenatal prophylaxis for all RHD negative women, the advantages of NIPD from the clinical and economic perspective are currently unclear. In particular, we have identified the following as important questions which will need to be addressed prior to implementation. First, is there a demonstrable clinical advantage of NIPD-based mass testing since the current situation in terms of preventing sensitisations (alloimmunisations) and adverse fetal outcomes is close to perfect? Second, can cost and supply of anti-D alone provide a rationale for NIPD test introduction, and how should missed cases be taken into account? Third, can NIPD implementation in reality be viewed as a simple extension of current RAADP programmes, or even a simple procedural substitution, with measurable efficiency gain? Finally, although adoption of the earlier developments listed above has largely been universal in Europe, is a similar general recommendation on NIPD possible for all population-based EU prenatal health systems? Our group is addressing these questions for 3 European countries, with the aim of providing information to support appropriate implementation of non-invasive detection of fetal RHD status. Equally importantly, our future work will help inform the difficult decisions which policy makers will face through NIPD developments in other areas such as Downs syndrome testing. Ala Szczepura, Professor Health Services Research, Clinical Sciences Institute, Warwick Medical School, University of Warwick, UK Gouke Bonsel, Professor Evaluation Health Care, Inst for Health Management & Policy; Dept Prenatal & Reproductive Care, Erasmus Medical Center, Rotterdam University, Netherlands Christian Krauth, Associate Professor Health Economics and Public Health, Institute for Epidemiology, Social Medicine & Health System Research, Hannover Medical School, Germany Leeza Osipenko, Senior Research Fellow, Clinical Sciences Institute, Warwick Medical School, University of Warwick, UK Alexander Haverkamp, Research Fellow, Dept. of Transfusion Medicine, Georg-August-University, Göttingen, Germany References 1. Finning K, Martin P, Summers J, Massey E, Poole G, Daniels G. Effect of high throughput RHD typing of fetal DNA in maternal plasma on use of anti-RhD immunoglobulin in RhD negative pregnant women: prospective feasibility study. BMJ 2008; 336: 816-818. 2. Kumar S. Universal RHD genotyping in fetuses. BMJ 2008 336: 783 -784. 3. “Foetal test rules out rhesus jab” http://news.bbc.co.uk/1/hi/health/7329108.stm (accessed 13/040/2008) 4. National Institute for Health and Clinical Excellence (NICE) 2002. Technology appraisal 41: Routine anti-D prophylaxis for pregnant women who are RhD negative. Available online at [http://www.nice.org.uk/page.aspx?o=31679]. 5. Chilcott J, Tappenden P, Jones ML, et al. The economics of routine antenatal anti-D prophylaxis for pregnant women who are rhesus negative. BJOG 2004; 111: 903-907. 6. Lyn S. Chitty, C. Ellen van der Schoot, Sinuhe Hahn, Neil D. Avent SAFE - The Special Non-invasive Advances in Fetal and Neonatal Evaluation Network: aims and achievements. Prenatal Diagnosis.2008; 28 (2): 83 - 88 7. Geifman-Holtzman O, Grotegut CA, Gaughan JP. Diagnostic accuracy of noninvasive fetal Rh genotyping from maternal blood--a meta-analysis. Am J Obstet Gynecol. 2006; 195(4): 1163-73. Competing interests: None declared |
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Geoff Daniels, Head of Molecualr Diagnostics IBGRL, NHS Blood and Transplant, Southmead Road, Bristol, BS9 4SB, UK, Kirstin Finning, Pete Martin, Joanna Summers, Edwin Massey, Geoff Poole
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In response to the letter by Szczepura et al. we wish to emphasise that our paper [1] on a high-throughput non-invasive test for predicting fetal RhD phenotype in RhD-negative pregnant women was scientific and made no claims about the economic benefit of introducing the technology. Szczepura et al. have posed a number of questions which we feel we should attempt to answer, at least in part. First, is there a demonstrable clinical advantage of non-invasive fetal diagnosis (NIPD)-based mass testing since the current situation in terms of preventing sensitisations and adverse fetal outcomes is close to perfect? The intention of our paper was not to suggest a means of reducing the rate of alloimmunisation; it was to provide an alternative methodology to achieving a similar high standard of care, and in doing so reducing exposure to blood products. Although the risk of transmitting infection through 'contaminated' blood products is very small indeed, it cannot be ignored, particularly when the recipient is a pregnant woman and not a hospital patient. Blood services world-wide are spending ever larger sums of money in order to ensure the safety of the blood supply. We suggest a way of significantly reducing the quantity of blood products given routinely to pregnant women. Second, can cost and supply of anti-RhD immunoglobulin alone provide a rationale for introduction of an NIPD screening test, and how should missed cases be taken into account? Cost and supply of anti-RhD alone at the moment might not provide a rationale, as supply is currently stable and the economic evaluation has not been undertaken (at least by us). As the rate of alloimmunisation to RhD falls and the costs of regulation increase, the costs of the product are also likely to increase. By 'missed cases' does Szczepura et al. mean false negatives? In our paper, the level of false negatives was very low and may have been much lower if all samples had been referred for analysis promptly. None of the three false- negative samples in our study would have been accepted under diagnostic conditions. We acknowledge that false negatives will probably occur at some point, but the largest improvement in the use of antenatal prophylaxis might come from a better management of the administration programme. In two hospitals in the UK, only about 86% of pregnant RhD- negative women received the recommended two doses of anti-RhD immunoglobulin [2]. It is likely that by knowing the fetal RhD type, mothers and midwifes will be more motivated to ensure compliance. Third, can NIPD implementation in reality be viewed as a simple extension of current routine antenatal anti-D prophylaxis (RAADP) programmes, or even a simple procedural substitution, with measurable efficiency gain? We have not proposed how the current RAADP programme would need to be changed or extended to facilitate the introduction of the mass screening test. We are currently evaluating the gestational age range at which a sample can be taken and give a reliable result in the test. There may well need to be a change in practice for taking prenatal samples. Finally, although adoption of the earlier developments listed above has largely been universal in Europe, is a similar general recommendation on NIPD possible for all population-based EU prenatal health systems? We do not know the answer to this question, but would observe that the standard of healthcare varies significantly across Europe. It is likely that those countries that currently enjoy a high standard of care would be able to introduce this method within existing healthcare pathway systems. We look forward to seeing publications from the socio-economic group of the SAFE Network of Excellence on the economic perspectives of NIPD- based screening of fetal RhD type in RhD-negative pregnant women. References 1. Finning K, Martin P, Summers J, Massey E, Poole G, Daniels G. Effect of high throughput RHD typing of fetal DNA in maternal plasma on use of anti-RhD immunoglobulin in RhD negative pregnant women: prospective feasibility study. Brit Med J 2008;336:816-818. 2. Chaffe B, Ford J, Bills V. Routine antenatal anti-D prophylaxis and patient compliance with the two-dose regimen. Transfus Med 2007;17:399 -403. Competing interests: None declared |
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