First-Trimester Screening for Down's Syndrome
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《新英格兰医药杂志》
To the Editor: Wapner and colleagues (Oct. 9 issue)1 describe implementation of the first-trimester combined test for trisomies 21 and 18 in 8514 women with a singleton pregnancy. They compare the performance of the Down's syndrome screening test (a detection rate of 79 percent with a false positive rate of 5 percent) with published estimates for the second-trimester triple and quadruple tests but not with the integrated test, although they cite the article describing the integrated test.2 They overlook the superior screening performance of the integrated test, which uses late first-trimester and early second-trimester markers together to obtain one screening result (original estimate, a detection rate of 94 percent with a false positive rate of 5 percent). SURUSS (the Serum, Urine and Ultrasound Screening Study), with data based on 47,053 pregnancies, confirmed this advantage, documenting a detection rate of 93 percent with a false positive rate of 5 percent3 — values close to the original estimates. The integrated test has higher detection rates than first-trimester screening and far fewer false positive results — for example, a 90 percent detection rate with a false positive rate of 2.6 percent, which doubles the safety by halving the number of women in whom an invasive diagnostic procedure is required. On the grounds of efficacy and safety, it is difficult to justify a place for first-trimester screening for Down's syndrome.
Editor's note: Dr. Wald reports holding a patent for the integrated test in the United States and Australia, having an application pending in other countries, and (with others) holding a patent in connection with the use of estriol as a second-trimester marker in prenatal screening for Down's syndrome. He is also director of a company (Logical Medical Systems) that produces software for the interpretation of Down's syndrome screening tests.
References
Wapner R, Thom E, Simpson JL, et al. First-trimester screening for trisomies 21 and 18. N Engl J Med 2003;349:1405-1413.
Wald NJ, Watt HC, Hackshaw AK. Integrated screening for Down's syndrome based on tests performed during the first and second trimesters. N Engl J Med 1999;341:461-467.
Wald NJ, Rodeck C, Hackshaw AK, Walters J, Chitty L, Mackinson AM. First and second trimester antenatal screening for Down's syndrome: the results of the Serum, Urine and Ultrasound Screening Study (SURUSS). Health Technol Assess 2003;7:1-77.
To the Editor: Reporting the results of a study of prenatal screening for Down's syndrome, Wapner et al. conclude that first-trimester screening based on the use of maternal serum markers in conjunction with measurement of fetal nuchal translucency has good sensitivity at an acceptable false positive rate. In their editorial on the article, Mennuti and Driscoll1 suggest that it is inappropriate or premature to offer first-trimester screening to women seeking early maternal care and that "second-trimester screening should remain the standard care."
We recently published data that bring additional support to that view. We established that the natural rate of loss of fetuses with Down's syndrome was higher in cases in which the chromosomal defect was detectable during prenatal screening than it was in cases in which the defect was undetectable.2 As a consequence, the rate of spontaneous miscarriage of fetuses with Down's syndrome as estimated by Morris et al.,3 which is the rate used by Wapner et al. to determine the sensitivity of their screening procedure, appears to be inadequate, since it relates to unselected populations of fetuses with Down's syndrome (i.e., populations with both detectable and undetectable defects).
Nathalie Leporrier, M.D.
Pierre Leymarie, M.D.
Michel Herrou, Ph.D.
Centre Hospitalier Universitaire de Caen
14000 Caen, France
References
Mennuti MT, Driscoll DA. Screening for Down's syndrome -- too many choices? N Engl J Med 2003;349:1471-1473.
Leporrier N, Herrou M, Morello R, Leymarie P. Fetuses with Down's syndrome detected by prenatal screening are more likely to abort spontaneously than fetuses with Down's syndrome not detected by prenatal screening. BJOG 2003;110:18-21.
Morris JK, Wald NJ, Watt HC. Fetal loss in Down syndrome pregnancies. Prenat Diagn 1999;19:142-145.
To the Editor: Mennuti and Driscoll acknowledge the advantages and effectiveness of screening for trisomy 21 by measurement of nuchal translucency and serum biochemical analysis at 11 to 14 weeks. However, they demand guidelines and quality control in measuring and interpreting nuchal translucency before this test is implemented in the United States. In the study by Wapner et al., scanning was performed by appropriately trained sonographers who complied with the criteria established in the early 1990s by the Fetal Medicine Foundation, which is a registered charity in the United Kingdom.1,2 The foundation has trained and provides quality assurance for several thousand doctors in many countries, including the United States.3
Kypros H. Nicolaides, M.D.
King's College Hospital
London SE5 9RS, United Kingdom
Editor's note: Dr. Nicolaides is chair of the Fetal Medicine Foundation.
References
Snijders RJM, Noble P, Sebire N, Souka A, Nicolaides KH. UK multicentre project on assessment of risk of trisomy 21 by maternal age and fetal nuchal-translucency thickness at 10-14 weeks of gestation. Lancet 1998;352:343-346.
Down's screening at 11-14 weeks. London: Fetal Medicine Foundation. (Accessed January 16, 2004, at http://www.fetalmedicine.com/f-downs.htm.)
Chasen ST, Sharma G, Kalish RB, Chervenak FA. First-trimester screening for aneuploidy with fetal nuchal translucency in a United States population. Ultrasound Obstet Gynecol 2003;22:149-151.
Dr. Wapner replies: My colleagues and I appreciate the comments about our article but believe they miss key points that strongly support screening for Down's syndrome in the first trimester. First, the technology of first-trimester screening is continuing to evolve; today's approach will be refined, and tomorrow's findings will change the debate. Second, and most important, is the consideration of women's preferences. The approach Dr. Wald proposes collects information in both the first and second trimesters but withholds risk evaluation until 16 weeks or later.1 Many women clearly prefer the earliest screening possible, irrespective of the likelihood that earlier testing may be slightly less efficient or may detect some pregnancies destined to miscarry.2,3,4 Withholding risk information during the first trimester presumably is predicated on the paternalistic belief that women might be confused by too many choices. Presumably, they would be relieved of that confusion if there were in fact no "place for first-trimester screening for Down's syndrome." Such comments not only suggest something that is untrue5 but may also be construed as patronizing. Pivotal to the debate is the psychological advantage of earlier reassurance as well as the relative safety of first-trimester termination of pregnancy.
In addition, Dr. Wald's approach requires multiple visits and reminders, posing logistical and financial drawbacks that adversely affect screening performance. In SURUSS, his own study, 15,278 of the 43,712 patients seen in the first trimester (35 percent) did not complete the multistep screening process.1 This group included half of those with a trisomy 21 pregnancy.
Dr. Leporrier and colleagues state that prenatal screening identifies some aneuploid fetuses that will spontaneously miscarry. Indeed, we took this into account in our analysis. Dr. Leporrier and colleagues' report confirms that most losses after first-trimester screening occur at a gestational age that would similarly affect second-trimester screening.5
In conclusion, screening for Down's syndrome surely must take into account women's preferences. We believe most will desire screening as early as possible. Others might prefer the slight additional detection offered by a combination of first- and second-trimester screening. In our opinion, at present, arbitrarily limiting access to a single approach is not to the benefit of patients.
Ronald J. Wapner, M.D.
Drexel University College of Medicine
Philadelphia, PA 19102
for the BUN Study Group
References
Wald NJ, Rodeck C, Hackshaw AK, Walters J, Chitty L, Mackinson AM. First and second trimester antenatal screening for Down's syndrome: the results of the Serum, Urine and Ultrasound Screening Study (SURUSS).
Health Technol Assess 2003;7:1-77.
de Graaf IM, Tijmstra T, Bleker OP, van Lith JMM. Women's preference in Down syndrome screening. Prenat Diagn 2002;22:624-629.
Mulvey S, Wallace EM. Women's knowledge of and attitudes to first and second trimester screening for Down's syndrome. BJOG 2000;107:1302-1305.
Mulvey S, Wallace EM. Reporting partial screening results: is it confusing and unsatisfactory? Prenat Diagn 2002;22:633-637.
Leporrier N, Herrou M, Morello R, Leymarie P. Fetuses with Down's syndrome detected by prenatal screening are more likely to abort spontaneously than fetuses with Down's syndrome not detected by prenatal screening. BJOG 2003;110:18-21.
The editorialists reply: We are aware of the availability of training, certification, and quality assurance for the measurement of nuchal translucency through the Fetal Medicine Foundation, as described by Dr. Nicolaides and by Dr. Wapner and colleagues in their report. The use of the criteria established by the Fetal Medicine Foundation was undoubtedly responsible for the level of consistency of nuchal-translucency measurements among centers and among individual women within centers in the study by Wapner et al.
It was our intention in the editorial to call attention to unanswered questions regarding first-trimester screening for Down's syndrome and to the difficulties inherent in performing and standardizing the measurement of nuchal translucency. We did not address the specifics of training, quality assurance, and practice guidelines because we believe that these are important issues for future consideration by the relevant professional organizations in the United States. We continue to believe that guidance from these organizations is needed before widespread implementation of first-trimester screening for Down's syndrome can be considered. Such guidance will also be useful at the local level to establish criteria for the credentialing of persons who wish to provide this service. Furthermore, in the United States, certification of physicians and maintenance of their certification, either in the broad range of specialty practice or in focused areas of practice, are appropriately the responsibility of the member boards of the American Board of Medical Specialties.
Michael T. Mennuti, M.D.
Deborah A. Driscoll, M.D.
University of Pennsylvania
Philadelphia, PA 19104
Related Article
by Mennuti, M. T.
Related Article
by Wapner, R.(Nicholas J. Wald, D.Sc.(M)
Editor's note: Dr. Wald reports holding a patent for the integrated test in the United States and Australia, having an application pending in other countries, and (with others) holding a patent in connection with the use of estriol as a second-trimester marker in prenatal screening for Down's syndrome. He is also director of a company (Logical Medical Systems) that produces software for the interpretation of Down's syndrome screening tests.
References
Wapner R, Thom E, Simpson JL, et al. First-trimester screening for trisomies 21 and 18. N Engl J Med 2003;349:1405-1413.
Wald NJ, Watt HC, Hackshaw AK. Integrated screening for Down's syndrome based on tests performed during the first and second trimesters. N Engl J Med 1999;341:461-467.
Wald NJ, Rodeck C, Hackshaw AK, Walters J, Chitty L, Mackinson AM. First and second trimester antenatal screening for Down's syndrome: the results of the Serum, Urine and Ultrasound Screening Study (SURUSS). Health Technol Assess 2003;7:1-77.
To the Editor: Reporting the results of a study of prenatal screening for Down's syndrome, Wapner et al. conclude that first-trimester screening based on the use of maternal serum markers in conjunction with measurement of fetal nuchal translucency has good sensitivity at an acceptable false positive rate. In their editorial on the article, Mennuti and Driscoll1 suggest that it is inappropriate or premature to offer first-trimester screening to women seeking early maternal care and that "second-trimester screening should remain the standard care."
We recently published data that bring additional support to that view. We established that the natural rate of loss of fetuses with Down's syndrome was higher in cases in which the chromosomal defect was detectable during prenatal screening than it was in cases in which the defect was undetectable.2 As a consequence, the rate of spontaneous miscarriage of fetuses with Down's syndrome as estimated by Morris et al.,3 which is the rate used by Wapner et al. to determine the sensitivity of their screening procedure, appears to be inadequate, since it relates to unselected populations of fetuses with Down's syndrome (i.e., populations with both detectable and undetectable defects).
Nathalie Leporrier, M.D.
Pierre Leymarie, M.D.
Michel Herrou, Ph.D.
Centre Hospitalier Universitaire de Caen
14000 Caen, France
References
Mennuti MT, Driscoll DA. Screening for Down's syndrome -- too many choices? N Engl J Med 2003;349:1471-1473.
Leporrier N, Herrou M, Morello R, Leymarie P. Fetuses with Down's syndrome detected by prenatal screening are more likely to abort spontaneously than fetuses with Down's syndrome not detected by prenatal screening. BJOG 2003;110:18-21.
Morris JK, Wald NJ, Watt HC. Fetal loss in Down syndrome pregnancies. Prenat Diagn 1999;19:142-145.
To the Editor: Mennuti and Driscoll acknowledge the advantages and effectiveness of screening for trisomy 21 by measurement of nuchal translucency and serum biochemical analysis at 11 to 14 weeks. However, they demand guidelines and quality control in measuring and interpreting nuchal translucency before this test is implemented in the United States. In the study by Wapner et al., scanning was performed by appropriately trained sonographers who complied with the criteria established in the early 1990s by the Fetal Medicine Foundation, which is a registered charity in the United Kingdom.1,2 The foundation has trained and provides quality assurance for several thousand doctors in many countries, including the United States.3
Kypros H. Nicolaides, M.D.
King's College Hospital
London SE5 9RS, United Kingdom
Editor's note: Dr. Nicolaides is chair of the Fetal Medicine Foundation.
References
Snijders RJM, Noble P, Sebire N, Souka A, Nicolaides KH. UK multicentre project on assessment of risk of trisomy 21 by maternal age and fetal nuchal-translucency thickness at 10-14 weeks of gestation. Lancet 1998;352:343-346.
Down's screening at 11-14 weeks. London: Fetal Medicine Foundation. (Accessed January 16, 2004, at http://www.fetalmedicine.com/f-downs.htm.)
Chasen ST, Sharma G, Kalish RB, Chervenak FA. First-trimester screening for aneuploidy with fetal nuchal translucency in a United States population. Ultrasound Obstet Gynecol 2003;22:149-151.
Dr. Wapner replies: My colleagues and I appreciate the comments about our article but believe they miss key points that strongly support screening for Down's syndrome in the first trimester. First, the technology of first-trimester screening is continuing to evolve; today's approach will be refined, and tomorrow's findings will change the debate. Second, and most important, is the consideration of women's preferences. The approach Dr. Wald proposes collects information in both the first and second trimesters but withholds risk evaluation until 16 weeks or later.1 Many women clearly prefer the earliest screening possible, irrespective of the likelihood that earlier testing may be slightly less efficient or may detect some pregnancies destined to miscarry.2,3,4 Withholding risk information during the first trimester presumably is predicated on the paternalistic belief that women might be confused by too many choices. Presumably, they would be relieved of that confusion if there were in fact no "place for first-trimester screening for Down's syndrome." Such comments not only suggest something that is untrue5 but may also be construed as patronizing. Pivotal to the debate is the psychological advantage of earlier reassurance as well as the relative safety of first-trimester termination of pregnancy.
In addition, Dr. Wald's approach requires multiple visits and reminders, posing logistical and financial drawbacks that adversely affect screening performance. In SURUSS, his own study, 15,278 of the 43,712 patients seen in the first trimester (35 percent) did not complete the multistep screening process.1 This group included half of those with a trisomy 21 pregnancy.
Dr. Leporrier and colleagues state that prenatal screening identifies some aneuploid fetuses that will spontaneously miscarry. Indeed, we took this into account in our analysis. Dr. Leporrier and colleagues' report confirms that most losses after first-trimester screening occur at a gestational age that would similarly affect second-trimester screening.5
In conclusion, screening for Down's syndrome surely must take into account women's preferences. We believe most will desire screening as early as possible. Others might prefer the slight additional detection offered by a combination of first- and second-trimester screening. In our opinion, at present, arbitrarily limiting access to a single approach is not to the benefit of patients.
Ronald J. Wapner, M.D.
Drexel University College of Medicine
Philadelphia, PA 19102
for the BUN Study Group
References
Wald NJ, Rodeck C, Hackshaw AK, Walters J, Chitty L, Mackinson AM. First and second trimester antenatal screening for Down's syndrome: the results of the Serum, Urine and Ultrasound Screening Study (SURUSS).
Health Technol Assess 2003;7:1-77.
de Graaf IM, Tijmstra T, Bleker OP, van Lith JMM. Women's preference in Down syndrome screening. Prenat Diagn 2002;22:624-629.
Mulvey S, Wallace EM. Women's knowledge of and attitudes to first and second trimester screening for Down's syndrome. BJOG 2000;107:1302-1305.
Mulvey S, Wallace EM. Reporting partial screening results: is it confusing and unsatisfactory? Prenat Diagn 2002;22:633-637.
Leporrier N, Herrou M, Morello R, Leymarie P. Fetuses with Down's syndrome detected by prenatal screening are more likely to abort spontaneously than fetuses with Down's syndrome not detected by prenatal screening. BJOG 2003;110:18-21.
The editorialists reply: We are aware of the availability of training, certification, and quality assurance for the measurement of nuchal translucency through the Fetal Medicine Foundation, as described by Dr. Nicolaides and by Dr. Wapner and colleagues in their report. The use of the criteria established by the Fetal Medicine Foundation was undoubtedly responsible for the level of consistency of nuchal-translucency measurements among centers and among individual women within centers in the study by Wapner et al.
It was our intention in the editorial to call attention to unanswered questions regarding first-trimester screening for Down's syndrome and to the difficulties inherent in performing and standardizing the measurement of nuchal translucency. We did not address the specifics of training, quality assurance, and practice guidelines because we believe that these are important issues for future consideration by the relevant professional organizations in the United States. We continue to believe that guidance from these organizations is needed before widespread implementation of first-trimester screening for Down's syndrome can be considered. Such guidance will also be useful at the local level to establish criteria for the credentialing of persons who wish to provide this service. Furthermore, in the United States, certification of physicians and maintenance of their certification, either in the broad range of specialty practice or in focused areas of practice, are appropriately the responsibility of the member boards of the American Board of Medical Specialties.
Michael T. Mennuti, M.D.
Deborah A. Driscoll, M.D.
University of Pennsylvania
Philadelphia, PA 19104
Related Article
by Mennuti, M. T.
Related Article
by Wapner, R.(Nicholas J. Wald, D.Sc.(M)