First, the term "triple-marker screening" is inaccurate, since double, triple and quadruple markers can be used. A non-numeric term, such as maternal serum screening, is preferable.
Maternal serum screening is part of a continuum of prenatal screening. In fact, such screening has been offered since the 1960s. The article did not discuss this extremely important point. The first screening criterion used for Down syndrome was the mother's age. If she was 35 years or over, she was offered amniocentesis. In the 1980s screening for the maternal serum a-fetoprotein (MSAFP) level was introduced, and in the 1990s multiple-marker screening was found to be the best screening tool available (Table 1). The article should have questioned why age is used as a screening criterion at all, not whether maternal serum screening is an appropriate alternative.
Maternal serum screening can provide women of all ages with an accurate assessment of the risk of Down syndrome. This allows mothers to choose whether to have a diagnostic test; it does not replace the diagnostic test. The authors were concerned that 21% to 31% of women with a positive result of a screening test decide against amniocentesis. It should be pointed out that many women who undergo maternal serum screening are hoping for reassurance.
We emphasize the need for women to receive sufficient information about maternal serum screening before having the test. In addition, before screening can be offered, adequate resources must be provided. In Ontario, a pilot maternal-serum-screening program has been in place since July 1, 1993. Experience with this program has shown that widespread use of maternal serum screening requires augmentation of existing genetic-counselling and laboratory services.
We feel that this article could have been improved by discussion of its contents with those participating in maternal-serum-screening programs. The introduction of maternal serum screening must be consistent with the principles of screening and should be undertaken only when the resources required for all aspects of such a program are available.
Sandra A. Farrell, MD, FRCPC, FCCMG
Diane E. Chadwick, PhD
Credit Valley Hospital
Mississauga, Ont.
Anne Marie Summers, MD, FRCPC, FCCMG
Philip R. Wyatt, MD, PhD
North York General Hospital
North York, Ont.
I was excited to read that the apparent sensitivity of triple-marker screening had been improved to the point that it had a rate of false-positive results of only 3.7%. This rate is supported in a table describing the results of four different studies of triple-marker screening.[1-4] Since I have been an opponent of this test, precisely because of its high rate of false-positive results, I decided to critically appraise and present this article to the local journal club.
Since the stated rate of false-positive results contradicted my own experience, I reviewed the four references that served as the basis for the rate cited. In fact, the rates cited were not the results of the triple-marker test alone but of the triple-marker test in conjunction with some form of confirmation of gestational age, most commonly a subsequent ultrasonographic examination. The rate of false-positive results before further evaluation in each of these studies was approximately double the rate after ultrasonographic confirmation. These findings are more consistent with the previously published data.
Although the article by Dick and the task force was published under the rubric of clinical practice guidelines, the abstract specifically states that "the economic issues involved are complex and were not considered." How can a practice guideline be considered useful if the economic aspects involved are not considered? This would be like suggesting that every patient with a headache undergo a computed tomography scan so that the risk of missing a brain tumour is reduced. It makes the Ottawa ankle rules practically irrelevant!
I am concerned about the impact of this guideline as published. I believe that it provides false credibility for a test that has serious limitations.
Gary Viner, BSc, MD, CCFP
Assistant professor
Department of Family Medicine
University of Ottawa
Ottawa, Ont.
References
Although the letters from Dr. Farrell and associates and Dr. Viner represent different perspectives on screening with the use of maternal serum markers, they both raise questions about the programmatic aspects of prenatal screening for Down syndrome. There also seems to be a misunderstanding of the role of the task force guidelines. Rather than being a practical guide to local prenatal services or programs, the recommendations should be viewed as a guide to the evidence supporting and effectiveness of these interventions according to the literature.
Viner questions the task force's recommendations for triple-marker screening involving maternal serum levels of alpha-fetoprotein, beta human chorionic gonadotropin and unconjugated estriol. He differentiates between the rate of false-positive results when the markers are used with and without confirmation of gestational age. As he notes, earlier studies of maternal serum markers without confirmation of gestational age reported higher rates of false-positive results. However, the task force used only the four recent studies for estimates of screening effectiveness.[1-4] These studies met the criteria for level II evidence and constituted the best available evidence.[5] The triple-marker screening in these studies included an ultrasonographic examination for confirmation of gestational age. Thus, the estimates cited in the task force recommendations reflect the screening intervention in toto (i.e., maternal serum markers with confirmation of gestational age), as delivered in a comprehensive screening program.
Farrell and associates suggest that the use of the term "triple-marker screening" is inaccurate. They correctly point out that screening with the use of maternal serum markers is evolving. However, they miss the point that triple-marker screening is the most effective combination to have undergone widespread evaluation in clinical trials. In keeping with the task force's emphasis on published evidence, the focus on triple-marker screening was deliberate and the use of the term accurate.
Farrell and associates believe that age should not be used as screening test. It is unclear, however, whether they are suggesting that there is no role for maternal age in counselling women concerning their options. It is true that, in comparison with triple-marker screening, age is not an appropriate screening criterion for all pregnant women. However, for women whose age or previous obstetric or genetic history puts them at a high risk of having a fetus with Down syndrome, there is evidence that amniocentesis or chorionic villus sampling, without triple-marker screening, is effective. When faced with the knowledge of their high risk, these women may choose to undergo these procedures directly, rather than undergo maternal serum-marker screening first. Therefore, the task force recommended that these women be identified and offered prenatal diagnosis. The task force also concluded that there was insufficient evidence that offering triple-marker screening (with amniocentesis in the case of a positive result) is preferable to offering amniocentesis or chorionic villus sampling on the basis of established risk factors (such as maternal age or a previous fetus with Down syndrome) alone.
Viner disagrees with the task force's decision not to review the economic aspects of screening for Down syndrome. However, discerning the impact of screening and diagnosis for Down syndrome is more complex than evaluating the yield or cost-effectiveness of radiographs for acute ankle injuries. Some studies suggest that prenatal screening and diagnosis of Down syndrome may reduce health care costs, given the current rates of termination of pregnancies involving fetuses with Down syndrome and the medical costs associated with care of people with Down syndrome. These studies also suggest that triple-marker screening may be less costly than prenatal diagnosis for women of advanced age.[2,6-8] Translating these studies into recommendations in the light of the social and ethical issues involved is not straightforward. Costs are no doubt considered by policymakers, who must decide whether there is sufficient social value or demand in the face of competing needs to justify a comprehensive screening program. However, once a program is available, the principal obligation of the physician is to make recommendations, based on an understanding of the effectiveness and benefit of the service, to the patients eligible for the service. Can a physician deny patients the opportunity to obtain an effective, available service on the basis of his or her own concern about the societal cost?
Finally, Farrell and associates state that the guidelines could have been improved by discussion of the contents with those participating in prenatal screening programs. The task force guidelines and recommendations are reviewed by or discussed with content and methodology experts of international stature when they are being formulated by the task force and when they are peer reviewed for publication. Unfortunately, there are always points of view that cannot be reconciled or included to everyone's satisfaction.
The task force developed these recommendations to help physicians who provide prenatal care decide whether to include these services in their regular practice. The recommendations indicate that triple-marker screening should be offered only as part of a comprehensive screening program and that the provision of information on the advantages and limitations of these interventions is essential. Program administrators are primarily responsible for ensuring that a prenatal-diagnosis program meets acceptable standards for the choice of assays, risk calculation, notification, counselling, gestational-age confirmation, referral and quality control. Individual physicians are responsible for learning about their local programs. The recommendations cannot perform these tasks. Furthermore, the task force does not base its recommendations on the economic or social implications of these programs but guides and informs physicians who are facing the availability of a comprehensive screening program and have patients who may wish to use it.
Paul T. Dick, MD, CM, FRCPC
Assistant professor
University of Toronto
Paediatric Outcomes Research Team
Division of General Paediatrics
Hospital for Sick Children
Toronto, Ont.
References