Choosing the Best Prenatal Screening Protocol
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《新英格兰医药杂志》
Prenatal genetic diagnosis for numerical chromosomal abnormalities (aneuploidy) was once simple. In the 1970s, women who were at least 35 years of age at delivery were offered an invasive procedure, amniocentesis, and 25 to 30 percent of trisomy 21 pregnancies were diagnosed. In the 1980s, the approach to screening changed because of observations that relatively low levels of alpha-fetoprotein and unconjugated estriol and relatively high levels of human chorionic gonadotropin and, later, inhibin A in the maternal serum during the second trimester predicted the risk of fetal trisomy. This information, together with the age-specific risk of trisomy, permitted individual risks during pregnancy to be calculated. If the risk exceeded a predetermined threshold, amniocentesis was offered, and 60 to 70 percent of pregnancies involving fetuses with trisomy 21 were identified.
A dazzling series of noninvasive screening options for trisomy 21 then evolved. An option during the first trimester consisted of ultrasonographic measurement of the diameter of fetal nuchal translucency (measures are increased in cases of trisomy 21), maternal serum pregnancy-associated plasma protein A (PAPP-A) (levels are decreased in cases of trisomy 21), and human chorionic gonadotropin (levels are increased in cases of trisomy 21). Protocols subsequently evolved for sequential screening involving first and second trimesters.
Our problem now is selecting the optimal protocol. Naturally, one hopes for a straightforward comparison on the basis of salient data from well-designed studies. But reports may wittingly or unwittingly be misleading. As the cutoff for the noninvasive screening test — above which a procedure is offered — is lowered, more invasive tests are done and the rate of detection (i.e., the sensitivity) of trisomy 21 increases.1 That is, detection increases with the number of procedures. The likelihood of detecting aneuploidy also increases with maternal age. Detection rates vary according to week of gestation and according to specific analytes. Thus, results can be presented in a more or less favorable light simply by choosing a particular week or number of procedures. Finally, some publications present theoretical models,2 which may not prove applicable in real life. Patients do not always cooperate.
Considerable experience has validated first-trimester screening. In a multicenter cohort study, 61 of 8514 women who underwent screening for Down's syndrome between 74 and 97 days of gestation had fetuses with Down's syndrome, and Wapner et al.3 identified a detection rate of 85 percent (with a procedure rate of 9 percent) on the basis of the levels of nuchal translucency (successfully measured in 99.5 percent of fetuses), PAPP-A, and human chorionic gonadotropin. Chorionic-villus sampling was offered when the risk estimated from these noninvasive tests exceeded 1 in 270 (the risk for a 35-year-old woman). If applied to the age distribution of the U.S. population, the detection rate would be 79 percent at a false positive rate of 5 percent.
Nicolaides4 calculated a detection rate of 87 percent for trisomy 21 in 44,613 pregnancies on the basis of the levels of nuchal translucency, PAPP-A, and human chorionic gonadotropin; the false positive rate was 5 percent. In 15,822 of the pregnancies, ultrasonographic evaluation of the nasal bone was also conducted; the bone was missing in 69 percent of fetuses with trisomy 21. Incorporating assessment of the nasal bone into calculations of the risk of trisomy 21 increased the detection rate to 97 percent at a procedure rate of 5 percent, or a detection rate of 91 percent with a 0.5 percent procedure rate. In another report from the same group, 30,564 patients were screened (according to measurements of the levels of nuchal translucency, PAPP-A, and human chorionic gonadotropin) and given results the same day; 93 percent of fetuses with trisomy 21 were identified.5
In this issue of the Journal, Malone et al.6 report results of the First- and Second-Trimester Evaluation of Risk (FASTER) Research Consortium trial, which was designed to compare various first-trimester or second-trimester noninvasive screening strategies for trisomy 21, analogous to the trial in the United Kingdom called SURUSS (Serum, Urine and Ultrasound Screening Study).7 In neither trial were first-trimester results disclosed to the patient, with the only exception being the 134 women in the FASTER trial whose fetuses had septated cystic hygromas. Among such women, 51 percent of fetuses showed chromosomal abnormalities and 34 percent had major structural anomalies.8 In FASTER, nuchal translucency could not be measured in 7 percent of pregnancies, leaving 36,120 women to be screened. If first-trimester screening results had been disclosed, 85 to 87 percent of fetuses with trisomy 21 would have been detected by 11 to 12 weeks, given a 5 percent false positive rate. Screening limited to the second trimester was less effective; the detection rate was 81 percent using four analytes (alpha-fetoprotein, human chorionic gonadotropin, unconjugated estriol, and inhibin A), and 69 percent using the popular "triple screen" (human chorionic gonadotropin, alpha-fetoprotein, and unconjugated estriol).
First-trimester screening is thus clearly superior to screening in the second trimester. The gap would probably widen if assessment of the nasal bone becomes incorporated in risk estimates. Although the FASTER group did not find assessment of the nasal bone helpful,9 the experience of others4,5,10 is different. First-trimester screening is practical. Measurements of nuchal translucency are accurate when a quality-assurance program exists. Chorionic-villus sampling is safe in experienced hands, with loss rates not differing significantly from those of amniocentesis.11 Pregnancy terminations are earlier, more private, and far safer than in the second trimester. The maternal death rate for first-trimester abortions is 1.1 per 100,000 abortions, as compared with 7 to 10 per 100,000 in the second trimester.12 Earlier is clearly better.
If first-trimester screening is good and second-trimester screening is within striking distance, why not first-plus-second-trimester screening? A key finding of the FASTER trial was that the highest detection rate should be achieved by sequential screening (i.e., screening in the first trimester and again in the second). The estimated detection rate for trisomy 21 with sequential screening — 95 to 96 percent — was 5 to 10 percent greater than detection rates with first-trimester screening alone in this cohort; however, the detection rate with the use of sequential screening was no better than the first-trimester detection rates of Avgidou et al.5 and Nicolaides4 (93 to 97 percent).
Sequential screening that offers only a single risk calculation after both first-trimester and second-trimester testing precludes safer, earlier terminations. Another problem is that an uncertain number of patients will return to complete the protocol. In the SURUSS trial, one third of subjects failed to return in the second trimester.7 If disclosing first-trimester results is proscribed, a woman might not return in timely fashion, oblivious of her already demonstrable high risk. The fear of litigation is obvious. Although a concern had been raised that disclosing first-trimester findings would reduce the sensitivity of screening tests (owing to removal of many abnormal cases before the second trimester), Cuckle and Arbuzova showed that disclosing first-trimester results leads to little loss in sensitivity.1
Serum screening and ultrasonography are not the only prenatal options. If the goal is detecting 100 percent of trisomies, why not proceed directly to chorionic-villus sampling or amniocentesis? In experienced hands, neither procedure seems to be as risky as once thought.11 In the FASTER trial, the procedure-related loss rate from amniocentesis was 0.15 percent.13 Universal invasive procedures would become more cost-effective as highly accurate chromosomal microarrarys14 complement and eventually replace traditional karyotypes. Whole-genome sequencing could soon be an affordable reality.
Definitive noninvasive prenatal diagnosis would require direct assessment of the final genome, rather than deductions based on results of fetal ultrasound or the hormone or protein levels in maternal serum. Direct approaches under study include analysis of intact fetal cells in maternal blood, cell-free DNA in maternal blood,15 or fetal trophoblasts exfoliated into the cervix.
In conclusion, pregnant women will now expect the option of first-trimester screening. If not available, it is prudent to permit a patient to pursue it elsewhere. Greater detection, by 5 to 10 percent, with sequential screening will appeal mostly to women desiring the maximum detection rates or the lowest procedure rates; however, incorporating evaluation of the nasal bone into a first-trimester assessment may increase detection rates sufficiently to make re-screening in the second trimester unnecessary. In the future, technical advances in screening may permit us to replace the plethora of noninvasive options with a simple, definitive noninvasive test. We can then return to the pleasing simplicity of the past.
Dr. Simpson reports having received honoraria for consulting from Biocept.
Source Information
From the Departments of Obstetrics and Gynecology and Molecular and Human Genetics, Baylor College of Medicine, Houston.
References
Cuckle HS, Arbuzova S. Multimarker maternal serum screening for chromosomal abnormalities. In: Milunsky A, ed. Genetic disorders and the fetus: diagnosis, prevention, and treatment. 5th ed. Baltimore: Johns Hopkins University Press, 2004:795-835.
Wald NJ, Watt HC, Hackshaw AK. Integrated screening for Down's syndrome on the basis of tests performed during the first and second trimesters. N Engl J Med 1999;341:461-467.
Wapner R, Thom E, Simpson JL, et al. First-trimester screening for trisomies 21 and 18. N Engl J Med 2003;349:1405-1413.
Nicolaides KH. Nuchal translucency and other first-trimester sonographic markers of chromosomal abnormalities. Am J Obstet Gynecol 2004;191:45-67.
Avgidou K, Papageorghiou A, Bindra R, Spencer K, Nicolaides KH. Prospective first-trimester screening for trisomy 21 in 30,564 pregnancies. Am J Obstet Gynecol 2005;192:1761-1767.
Malone FD, Canick JA, Ball RH, et al. First-trimester or second-trimester screening, or both, for Down's syndrome. N Engl J Med 2005;353:2001-2011.
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). J Med Screen 2003;10:56-104.
Malone FD, Ball RH, Nyberg DA, et al. First-trimester septated cystic hygroma: prevalence, natural history, and pediatric outcome. Obstet Gynecol 2005;106:288-294.
Malone FD, Ball RH, Nyberg DA, et al. First-trimester nasal bone evaluation for aneuploidy in the general population. Obstet Gynecol 2004;104:1222-1228.
Odibo AO, Sehdev HM, Dunn L, McDonald R, Macones GA. The association between fetal nasal bone hypoplasia and aneuploidy. Obstet Gynecol 2004;104:1229-1233.
Simpson JL, Elias S. Genetics in obstetrics and gynecology. 3rd ed. Philadelphia: Saunders, 2003:345-55.
Lawson HW, Frye A, Atrash HK, Smith JC, Shulman HB, Ramick M. Abortion mortality, United States, 1972 through 1987. Am J Obstet Gynecol 1994;171:1365-1372.
Eddleman K, Berkowitz R, Kharbutli Y, et al. Pregnancy loss rates after midtrimester amniocentesis: the FASTER trial. Am J Obstet Gynecol 2003;189:Suppl:S111-S111. abstract.
Cheung SW, Shaw CA, Yu W, et al. Development and validation of a CGH microarray for clinical cytogenetic diagnosis. Genet Med 2005;7:422-432.
Bianchi DW, Simpson JL, Jackson LG, et al. Fetal gender and aneuploidy detection using fetal cells in maternal blood: analysis of NIFTY I data: National Institute of Child Health and Development Fetal Cell Isolation Study. Prenat Diagn 2002;22:609-615.(Joe Leigh Simpson, M.D.)
A dazzling series of noninvasive screening options for trisomy 21 then evolved. An option during the first trimester consisted of ultrasonographic measurement of the diameter of fetal nuchal translucency (measures are increased in cases of trisomy 21), maternal serum pregnancy-associated plasma protein A (PAPP-A) (levels are decreased in cases of trisomy 21), and human chorionic gonadotropin (levels are increased in cases of trisomy 21). Protocols subsequently evolved for sequential screening involving first and second trimesters.
Our problem now is selecting the optimal protocol. Naturally, one hopes for a straightforward comparison on the basis of salient data from well-designed studies. But reports may wittingly or unwittingly be misleading. As the cutoff for the noninvasive screening test — above which a procedure is offered — is lowered, more invasive tests are done and the rate of detection (i.e., the sensitivity) of trisomy 21 increases.1 That is, detection increases with the number of procedures. The likelihood of detecting aneuploidy also increases with maternal age. Detection rates vary according to week of gestation and according to specific analytes. Thus, results can be presented in a more or less favorable light simply by choosing a particular week or number of procedures. Finally, some publications present theoretical models,2 which may not prove applicable in real life. Patients do not always cooperate.
Considerable experience has validated first-trimester screening. In a multicenter cohort study, 61 of 8514 women who underwent screening for Down's syndrome between 74 and 97 days of gestation had fetuses with Down's syndrome, and Wapner et al.3 identified a detection rate of 85 percent (with a procedure rate of 9 percent) on the basis of the levels of nuchal translucency (successfully measured in 99.5 percent of fetuses), PAPP-A, and human chorionic gonadotropin. Chorionic-villus sampling was offered when the risk estimated from these noninvasive tests exceeded 1 in 270 (the risk for a 35-year-old woman). If applied to the age distribution of the U.S. population, the detection rate would be 79 percent at a false positive rate of 5 percent.
Nicolaides4 calculated a detection rate of 87 percent for trisomy 21 in 44,613 pregnancies on the basis of the levels of nuchal translucency, PAPP-A, and human chorionic gonadotropin; the false positive rate was 5 percent. In 15,822 of the pregnancies, ultrasonographic evaluation of the nasal bone was also conducted; the bone was missing in 69 percent of fetuses with trisomy 21. Incorporating assessment of the nasal bone into calculations of the risk of trisomy 21 increased the detection rate to 97 percent at a procedure rate of 5 percent, or a detection rate of 91 percent with a 0.5 percent procedure rate. In another report from the same group, 30,564 patients were screened (according to measurements of the levels of nuchal translucency, PAPP-A, and human chorionic gonadotropin) and given results the same day; 93 percent of fetuses with trisomy 21 were identified.5
In this issue of the Journal, Malone et al.6 report results of the First- and Second-Trimester Evaluation of Risk (FASTER) Research Consortium trial, which was designed to compare various first-trimester or second-trimester noninvasive screening strategies for trisomy 21, analogous to the trial in the United Kingdom called SURUSS (Serum, Urine and Ultrasound Screening Study).7 In neither trial were first-trimester results disclosed to the patient, with the only exception being the 134 women in the FASTER trial whose fetuses had septated cystic hygromas. Among such women, 51 percent of fetuses showed chromosomal abnormalities and 34 percent had major structural anomalies.8 In FASTER, nuchal translucency could not be measured in 7 percent of pregnancies, leaving 36,120 women to be screened. If first-trimester screening results had been disclosed, 85 to 87 percent of fetuses with trisomy 21 would have been detected by 11 to 12 weeks, given a 5 percent false positive rate. Screening limited to the second trimester was less effective; the detection rate was 81 percent using four analytes (alpha-fetoprotein, human chorionic gonadotropin, unconjugated estriol, and inhibin A), and 69 percent using the popular "triple screen" (human chorionic gonadotropin, alpha-fetoprotein, and unconjugated estriol).
First-trimester screening is thus clearly superior to screening in the second trimester. The gap would probably widen if assessment of the nasal bone becomes incorporated in risk estimates. Although the FASTER group did not find assessment of the nasal bone helpful,9 the experience of others4,5,10 is different. First-trimester screening is practical. Measurements of nuchal translucency are accurate when a quality-assurance program exists. Chorionic-villus sampling is safe in experienced hands, with loss rates not differing significantly from those of amniocentesis.11 Pregnancy terminations are earlier, more private, and far safer than in the second trimester. The maternal death rate for first-trimester abortions is 1.1 per 100,000 abortions, as compared with 7 to 10 per 100,000 in the second trimester.12 Earlier is clearly better.
If first-trimester screening is good and second-trimester screening is within striking distance, why not first-plus-second-trimester screening? A key finding of the FASTER trial was that the highest detection rate should be achieved by sequential screening (i.e., screening in the first trimester and again in the second). The estimated detection rate for trisomy 21 with sequential screening — 95 to 96 percent — was 5 to 10 percent greater than detection rates with first-trimester screening alone in this cohort; however, the detection rate with the use of sequential screening was no better than the first-trimester detection rates of Avgidou et al.5 and Nicolaides4 (93 to 97 percent).
Sequential screening that offers only a single risk calculation after both first-trimester and second-trimester testing precludes safer, earlier terminations. Another problem is that an uncertain number of patients will return to complete the protocol. In the SURUSS trial, one third of subjects failed to return in the second trimester.7 If disclosing first-trimester results is proscribed, a woman might not return in timely fashion, oblivious of her already demonstrable high risk. The fear of litigation is obvious. Although a concern had been raised that disclosing first-trimester findings would reduce the sensitivity of screening tests (owing to removal of many abnormal cases before the second trimester), Cuckle and Arbuzova showed that disclosing first-trimester results leads to little loss in sensitivity.1
Serum screening and ultrasonography are not the only prenatal options. If the goal is detecting 100 percent of trisomies, why not proceed directly to chorionic-villus sampling or amniocentesis? In experienced hands, neither procedure seems to be as risky as once thought.11 In the FASTER trial, the procedure-related loss rate from amniocentesis was 0.15 percent.13 Universal invasive procedures would become more cost-effective as highly accurate chromosomal microarrarys14 complement and eventually replace traditional karyotypes. Whole-genome sequencing could soon be an affordable reality.
Definitive noninvasive prenatal diagnosis would require direct assessment of the final genome, rather than deductions based on results of fetal ultrasound or the hormone or protein levels in maternal serum. Direct approaches under study include analysis of intact fetal cells in maternal blood, cell-free DNA in maternal blood,15 or fetal trophoblasts exfoliated into the cervix.
In conclusion, pregnant women will now expect the option of first-trimester screening. If not available, it is prudent to permit a patient to pursue it elsewhere. Greater detection, by 5 to 10 percent, with sequential screening will appeal mostly to women desiring the maximum detection rates or the lowest procedure rates; however, incorporating evaluation of the nasal bone into a first-trimester assessment may increase detection rates sufficiently to make re-screening in the second trimester unnecessary. In the future, technical advances in screening may permit us to replace the plethora of noninvasive options with a simple, definitive noninvasive test. We can then return to the pleasing simplicity of the past.
Dr. Simpson reports having received honoraria for consulting from Biocept.
Source Information
From the Departments of Obstetrics and Gynecology and Molecular and Human Genetics, Baylor College of Medicine, Houston.
References
Cuckle HS, Arbuzova S. Multimarker maternal serum screening for chromosomal abnormalities. In: Milunsky A, ed. Genetic disorders and the fetus: diagnosis, prevention, and treatment. 5th ed. Baltimore: Johns Hopkins University Press, 2004:795-835.
Wald NJ, Watt HC, Hackshaw AK. Integrated screening for Down's syndrome on the basis of tests performed during the first and second trimesters. N Engl J Med 1999;341:461-467.
Wapner R, Thom E, Simpson JL, et al. First-trimester screening for trisomies 21 and 18. N Engl J Med 2003;349:1405-1413.
Nicolaides KH. Nuchal translucency and other first-trimester sonographic markers of chromosomal abnormalities. Am J Obstet Gynecol 2004;191:45-67.
Avgidou K, Papageorghiou A, Bindra R, Spencer K, Nicolaides KH. Prospective first-trimester screening for trisomy 21 in 30,564 pregnancies. Am J Obstet Gynecol 2005;192:1761-1767.
Malone FD, Canick JA, Ball RH, et al. First-trimester or second-trimester screening, or both, for Down's syndrome. N Engl J Med 2005;353:2001-2011.
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). J Med Screen 2003;10:56-104.
Malone FD, Ball RH, Nyberg DA, et al. First-trimester septated cystic hygroma: prevalence, natural history, and pediatric outcome. Obstet Gynecol 2005;106:288-294.
Malone FD, Ball RH, Nyberg DA, et al. First-trimester nasal bone evaluation for aneuploidy in the general population. Obstet Gynecol 2004;104:1222-1228.
Odibo AO, Sehdev HM, Dunn L, McDonald R, Macones GA. The association between fetal nasal bone hypoplasia and aneuploidy. Obstet Gynecol 2004;104:1229-1233.
Simpson JL, Elias S. Genetics in obstetrics and gynecology. 3rd ed. Philadelphia: Saunders, 2003:345-55.
Lawson HW, Frye A, Atrash HK, Smith JC, Shulman HB, Ramick M. Abortion mortality, United States, 1972 through 1987. Am J Obstet Gynecol 1994;171:1365-1372.
Eddleman K, Berkowitz R, Kharbutli Y, et al. Pregnancy loss rates after midtrimester amniocentesis: the FASTER trial. Am J Obstet Gynecol 2003;189:Suppl:S111-S111. abstract.
Cheung SW, Shaw CA, Yu W, et al. Development and validation of a CGH microarray for clinical cytogenetic diagnosis. Genet Med 2005;7:422-432.
Bianchi DW, Simpson JL, Jackson LG, et al. Fetal gender and aneuploidy detection using fetal cells in maternal blood: analysis of NIFTY I data: National Institute of Child Health and Development Fetal Cell Isolation Study. Prenat Diagn 2002;22:609-615.(Joe Leigh Simpson, M.D.)