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What is the role of fetal nasal bone examination in the assessment of risk for trisomy 21 in clinical practice?
American Journal of Obstetrics and Gynecology (2006) 195, 1–3
www.ajog.org
EDITORIAL
What is the role of fetal nasal bone examination in the assessment of risk for trisomy 21 in clinical practice? Yves Ville, MD, PhD* Paris-Ile-de-France-Ouest Medical School, CHI Poissy, France
The initial promise Lack of visualization of the fetal nasal bones (NB) with ultrasound at 11 to 14 weeks of gestation has been proposed as a marker for trisomy 21.1 Nonvisualization of the NB was reported to detect up to 69% of cases of trisomy 21 with a false-positive rate of 2.8%.1 Subsequent studies with appropriate follow-up confirmed the value of this sonographic marker: the detection rates ranged from 35% to 73% and the false-positive rates from 0.5% to 2.5%.2-6 These results were obtained by assessing whether or not fetal nasal bones were ‘‘present’’ or ‘‘absent.’’ The story, however, is more complicated than that. There is discordance between an ‘‘absent’’ NB assessed by ultrasound and the radiologic and histologic findings.7 Moreover, the prevalence of an ‘‘absent’’ NB in both euploid and aneuploid fetuses has been reported to decrease as the crown-rump-length (CRL) increases. This unexpected phenomenon has been attributed to delayed development and maturation of the nasal bones, which presumably catch up with advancing gestation. Therefore, it is more appropriate to refer to ‘‘nonvisualization’’ of NB rather than to their ‘‘absence.’’ The optimal gestation for NB evaluation appears to be that at which the CRL ranges from 65 to 74 mm.3,6-9 The early studies on fetal NB with ultrasound, widely perceived as cutting-edge clinical research, raised many questions. Key issues were the reproducibility of the
technique, its diagnostic value, as well as its precise role as a method of risk assessment in clinical practice.
Standardization of the examination Standardization of NB imaging is a critical step. The fetal face should be viewed longitudinally and precisely in the midline. This can be accomplished by ensuring that the metopic suture, which completely separates the frontal bones during early pregnancy, is perfectly aligned with the ultrasound beam. When this is the case, the frontal bones are not visualized in midsagittal views of the facial profile.9 It has also been proposed that 3D ultrasound may facilitate visualization of the midsagittal plane and provide additional diagnostic information, such as identification of unilateral absence or asymmetric development of the nasal bones.11-14 The nasal bone synostosis is characterized by a thin echogenic line within the bridge of the nose. The nasal bones are considered to be present if this line is more echogenic than the overlying skin, and absent if it is either not visible or its echogenicity is the same or less than that of the skin.15 Although examination of the NB is usually combined with nuchal translucency measurement, optimal imaging is best demonstrated in the same view while by modifying the angle of insonation to become perpendicular to the nasal bridge.1,15,16
Some disappointing results * Reprint requests: Yves Ville, Paris-Ile-de-France-Ouest Medical School, CHI Poissy, France. E-mail: [email protected] 0002-9378/$ - see front matter Ó 2006 Mosby, Inc. All rights reserved. doi:10.1016/j.ajog.2006.03.104
Although low false-positive rates were consistently reported in the initial studies, uncertainty about the visualization of the NB (or lack thereof) or improper
2 assessment of the sign resulted in detection rates that ranged between less than 2% and 31%. This is a ‘‘hidden downside’’ of the sign, especially if examination of at least 120 cases is required for proficiency.17 Reproducible results are dependent upon stringent technical requirements, extensive training, and continuous experience. It is noteworthy that extended previous experience in obstetric ultrasound and even in NT assessment is not sufficient for proficiency in imaging of the fetal nasal bone.19 Imaging of the nasal bones confers risk for trisomy 21, which is independent of other factors (maternal age, serum biochemistry, and nuchal translucency). In euploid fetuses, visualization of the fetal NB in the first trimester of pregnancy was demonstrated to be an independent risk factor for trisomy 21 from maternal age (MA), NT, and maternal serum markers (MSM). This observation made possible the development of the concept that the NB sign could be combined with other parameters for risk assessment purposes (using likelihood ratios adjusted for ethnicity and CRL20). In 2 largely unselected populations of over 6000 and 20,000 cases respectively,9,18 NB assessment (when performed at the time of NT measurement) proved to have a false-positive rate of less than 1%. However, the detection rate for trisomy 21 varied widely (between 7.7% and 62.1%). Two important factors may explain the difference between the studies. In 1 study, technical guidelines, training, and proficiency of the operators have been questioned since the NB was not assessed in 25% of the cases.9 In the other study, the mean MA of participants was 35 years. The data obtained from the latter study were modelled so that it could be implemented in a younger population.18 In pregnancies with a normal karyotype, advanced maternal age and larger NT measurements were associated with an increased incidence of nonvisualization of the NB. For example, the likelihood of an ‘‘absent’’ NB was 7 times higher if the maternal age was 40 years and the fetal NT was 2 mm above the mean of that observed in a 25-year-old woman with NT at the 50th centile.18 The absence of a persuasive explanation for this association raised the possibility that assessment of the NB could be subjective and a function of the previous probability of trisomy 21 based upon other clinical factors.
What is the value of the NB in risk assessment of trisomy 21 in clinical practice? The complexity of NB assessment and the rigor required to maintain the skills, together with the potential for a subjective assessment, are limitations for the implementation of NB as a 1-step risk assessment procedure performed at the time of NT measurement. Therefore, it is unlikely that assessment of the fetal NB would be a
Ville universal risk assessment tool. On the other hand, we believe that the characteristics of the test make it an excellent candidate for contingency assessment for trisomy 21 in early pregnancy. Why? The term ‘‘contingency screening’’ refers to a program in which first-trimester risk assessment is complemented with a second test. The subsequent test could be a second trimester ultrasound, maternal serum markers, or other approaches. It is clear that imaging of the NB is unlikely to be part of the initial assessment. However, the test has the characteristics to be a second line screening that can be performed in early pregnancy. Indeed, the combination of NT, maternal age, and serum biochemistry can be used to classify the population into high, intermediate, and low risk. The intermediate risk group can then be studied with the NB. This program yields comparable results to those of an integrated screening, which include tests in the second trimester. The main advantage is that risk assessment is completed earlier in pregnancy. Fetal NB assessment would only need to be offered to 10% to 25% of the entire population participating in risk assessment (depending on the cut-off chosen to define those with intermediate risks).22 A similar approach has been proposed in the US for women at intermediate risk in the second trimester.23 Using this approach, even a high false-positive rate for the fetal NB in the intermediate risk group would not jeopardize the performance of the risk assessment program for the entire population. This is 1 of the main contributions of the study by Cicero et al, which is reported in this issue of the Journal. They propose that first trimester assessment be performed with combined NT and MSM at 11 to 14 weeks, and then offer fetal NB to the 10% of the population with an intermediate risk defined as ranging between 1/100 and 1/1000.18 Allocation of resources for risk assessment for all pregnant women in the first trimester for trisomy 21 by combining NT and MSM is cost-effective when the expenditure of ultrasound can be met locally24 and can, therefore, be offered to all women as an integral part of prenatal care. The concept of specialized units, where a second level of screening can be performed either in the first or second trimester to derive a new integrated risk assessment, appears to be the way of the future. This approach would ensure respect of women’s autonomy by avoiding unnecessary invasive testing or the ethical issues related to nondisclosure of early results while waiting for a second test in the midtrimester in the context of sequential screening.
References 1. Cicero S, Curcio P, Papageorghiou A, Sonek J, Nicolaides KH. Absence of nasal bone in fetuses with trisomy 21 at 11-14 weeks of gestation: an observational study. Lancet 2001;358:1665-7.
Ville 2. Minderer S, Gloning KP, Henrich W, Stoger H. The nasal bone in fetuses with trisomy 21: sonographic versus pathomorphological findings. Ultrasound Obstet Gynecol 2003;22:16-21. 3. Otano L, Aiello H, Igarzabal L, Matayoshi T, Gadow EC. Association between first trimester absence of fetal nasal bone on ultrasound and Down syndrome. Prenat Diagn 2002;22:930-2. 4. Orlandi F, Bilardo CM, Campogrande M, Krantz D, Hallahan T, Rossi C, et al. Measurement of nasal bone length at 11-14 weeks of pregnancy and its potential role in Down syndrome risk assessment. Ultrasound Obstet Gynecol 2003;22:36-9. 5. Viora E, Masturzo B, Errange G, Sciarrone A, Bastonero S, Campogrande M. Ultrasound evaluation of fetal nasal bone at 11 to 14 weeks in a consecutive series of 1906 fetuses. Prenat Diagn 2003;23:784-7. 6. Cicero S, Rembouskos G, Vandecruys H, Hogg M, Nicolaides KH. Likelihood ratio for trisomy 21 in fetuses with absent nasal bone at the 11-14-week scan. Ultrasound Obstet Gynecol 2004;23:218-23. 7. Larose C, Massoc P, Hillion Y, Bernard JP, Ville Y. Comparison of fetal nasal bone assessment by ultrasound at 11-14 weeks and by postmortem X-ray in trisomy 21: a prospective observational study. Ultrasound Obstet Gynecol 2003;22:27-30. 8. Zoppi MA, Ibba RM, Axiana C, Floris M, Manca F, Monni G. Absence of fetal nasal bone and aneuploidies at first trimester nuchal translucency screening in unselected pregnancies. Prenat Diagn 2003;23:496-500. 9. Malone FD, Ball RH, Nyberg DA, Comstock CH, Saade G, Berkowitz RL, et al. FASTER Research Consortium. First-trimester nasal bone evaluation for aneuploidy in the general population. Obstet Gynecol 2004;104:1222-8. 10. Goncalves LF, Espinoza J, Lee W, Romero R. Should the frontal bone be visualized in midline sagittal views of the facial profile to assess the fetal nasal bones during the first trimester? Ultrasound Obstet Gynecol 2005;25:90-4. 11. Lee W, DeVore GR, Comstock CH, Kalache KD, McNie B, Chaiworapongsa T, et al. Nasal bone evaluation in fetuses with Down syndrome during the second and third trimesters of pregnancy. J Ultrasound Med 2003;22:55-60. 12. Goncalves LF, Espinoza J, Lee W, Schoen ML, Devers P, Mazor M, et al. Phenotypic characteristics of absent and hypoplastic nasal bones in fetuses with Down syndrome: description by 3-dimensional ultrasonography and clinical significance. J Ultrasound Med 2004;23:1619-27.
3 13. Benoit B, Chaoui R. Three-dimensional ultrasound with maximal mode rendering: a novel technique for the diagnosis of bilateral or unilateral absence or hypoplasia of nasal bones in second-trimester screening for Down syndrome. Ultrasound Obstet Gynecol 2005; 25:19-24. 14. Peralta CF, Falcon O, Wegrzyn P, Faro C, Nicolaides KH. Assessment of the gap between the fetal nasal bones at 11 to 13 C 6 weeks of gestation by three-dimensional ultrasound. Ultrasound Obstet Gynecol 2005;25:464-7. 15. Sonek JD. Nasal bone evaluation with ultrasonography: a marker for fetal aneuploidy. Ultrasound Obstet Gynecol 2003;22:11-5. 16. Cicero S, Rembouskos G, Vandecruys H, Hogg M, Nicolaides KH. Likelihood ratio for Trisomy 21 in fetuses with absent nasal bone at the 11-14 weeks scan. Ultrasound Obstet Gynecol 2004; 23:218-23. 17. Cicero S, Dezerega V, Andrade E, Scheier M, Nicolaides KH. Learning curve for sonographic examination of the fetal nasal bone at 11-14 weeks. Ultrasound Obstet Gynecol 2003;22:135-7. 18. Cicero S, Avgidou K, Rembouskos G, Kagan KO, Nicolaides KH. Nasal bone in first-trimester screening for trisomy 21. Am J Obstet Gynecol 2006; in press. 19. Senat MV, Bernard JP, Boulvain M, Ville Y. Intra- and interoperator variability in fetal nasal bone assessment at 11-14 weeks of gestation. Ultrasound Obstet Gynecol 2003;22:138-41. 20. Cicero S, Sonek J, McKenna D, Croom C, Johnson L, Nicolaides KH. Nasal bone hypoplasia in fetuses with trisomy 21. Ultrasound Obstet Gynecol 2003;21:15-8. 21. Cicero S, Spencer K, Avgidou K, Faiola S, Nicolaides KH. Maternal serum biochemistry at 11-13(C6) weeks in relation to the presence or absence of the fetal nasal bone on ultrasonography in chromosomally abnormal fetuses: an updated analysis of integrated ultrasound and biochemical screening. Prenat Diagn 2005;25:977-83. 22. Wright D, Bradbury I, Benn P, Cuckle H, Ritchie K. Contingent screening for Down syndrome is an efficient alternative to nondisclosure sequential screening. Prenat Diagn 2004;24:762-6. 23. DeVore GR, Romero R. Genetic sonography: an option for women of advanced maternal age with negative triple-marker maternal serum screening results. J Ultrasound Med 2003;22:1191-9. 24. Odibo AO, Stamilio DM, Nelson DB, Sehdev HM, Macones GA. A cost-effectiveness analysis of prenatal screening strategies for Down syndrome. Obstet Gynecol 2005;106:562-8.
www.ajog.org
EDITORIAL
What is the role of fetal nasal bone examination in the assessment of risk for trisomy 21 in clinical practice? Yves Ville, MD, PhD* Paris-Ile-de-France-Ouest Medical School, CHI Poissy, France
The initial promise Lack of visualization of the fetal nasal bones (NB) with ultrasound at 11 to 14 weeks of gestation has been proposed as a marker for trisomy 21.1 Nonvisualization of the NB was reported to detect up to 69% of cases of trisomy 21 with a false-positive rate of 2.8%.1 Subsequent studies with appropriate follow-up confirmed the value of this sonographic marker: the detection rates ranged from 35% to 73% and the false-positive rates from 0.5% to 2.5%.2-6 These results were obtained by assessing whether or not fetal nasal bones were ‘‘present’’ or ‘‘absent.’’ The story, however, is more complicated than that. There is discordance between an ‘‘absent’’ NB assessed by ultrasound and the radiologic and histologic findings.7 Moreover, the prevalence of an ‘‘absent’’ NB in both euploid and aneuploid fetuses has been reported to decrease as the crown-rump-length (CRL) increases. This unexpected phenomenon has been attributed to delayed development and maturation of the nasal bones, which presumably catch up with advancing gestation. Therefore, it is more appropriate to refer to ‘‘nonvisualization’’ of NB rather than to their ‘‘absence.’’ The optimal gestation for NB evaluation appears to be that at which the CRL ranges from 65 to 74 mm.3,6-9 The early studies on fetal NB with ultrasound, widely perceived as cutting-edge clinical research, raised many questions. Key issues were the reproducibility of the
technique, its diagnostic value, as well as its precise role as a method of risk assessment in clinical practice.
Standardization of the examination Standardization of NB imaging is a critical step. The fetal face should be viewed longitudinally and precisely in the midline. This can be accomplished by ensuring that the metopic suture, which completely separates the frontal bones during early pregnancy, is perfectly aligned with the ultrasound beam. When this is the case, the frontal bones are not visualized in midsagittal views of the facial profile.9 It has also been proposed that 3D ultrasound may facilitate visualization of the midsagittal plane and provide additional diagnostic information, such as identification of unilateral absence or asymmetric development of the nasal bones.11-14 The nasal bone synostosis is characterized by a thin echogenic line within the bridge of the nose. The nasal bones are considered to be present if this line is more echogenic than the overlying skin, and absent if it is either not visible or its echogenicity is the same or less than that of the skin.15 Although examination of the NB is usually combined with nuchal translucency measurement, optimal imaging is best demonstrated in the same view while by modifying the angle of insonation to become perpendicular to the nasal bridge.1,15,16
Some disappointing results * Reprint requests: Yves Ville, Paris-Ile-de-France-Ouest Medical School, CHI Poissy, France. E-mail: [email protected] 0002-9378/$ - see front matter Ó 2006 Mosby, Inc. All rights reserved. doi:10.1016/j.ajog.2006.03.104
Although low false-positive rates were consistently reported in the initial studies, uncertainty about the visualization of the NB (or lack thereof) or improper
2 assessment of the sign resulted in detection rates that ranged between less than 2% and 31%. This is a ‘‘hidden downside’’ of the sign, especially if examination of at least 120 cases is required for proficiency.17 Reproducible results are dependent upon stringent technical requirements, extensive training, and continuous experience. It is noteworthy that extended previous experience in obstetric ultrasound and even in NT assessment is not sufficient for proficiency in imaging of the fetal nasal bone.19 Imaging of the nasal bones confers risk for trisomy 21, which is independent of other factors (maternal age, serum biochemistry, and nuchal translucency). In euploid fetuses, visualization of the fetal NB in the first trimester of pregnancy was demonstrated to be an independent risk factor for trisomy 21 from maternal age (MA), NT, and maternal serum markers (MSM). This observation made possible the development of the concept that the NB sign could be combined with other parameters for risk assessment purposes (using likelihood ratios adjusted for ethnicity and CRL20). In 2 largely unselected populations of over 6000 and 20,000 cases respectively,9,18 NB assessment (when performed at the time of NT measurement) proved to have a false-positive rate of less than 1%. However, the detection rate for trisomy 21 varied widely (between 7.7% and 62.1%). Two important factors may explain the difference between the studies. In 1 study, technical guidelines, training, and proficiency of the operators have been questioned since the NB was not assessed in 25% of the cases.9 In the other study, the mean MA of participants was 35 years. The data obtained from the latter study were modelled so that it could be implemented in a younger population.18 In pregnancies with a normal karyotype, advanced maternal age and larger NT measurements were associated with an increased incidence of nonvisualization of the NB. For example, the likelihood of an ‘‘absent’’ NB was 7 times higher if the maternal age was 40 years and the fetal NT was 2 mm above the mean of that observed in a 25-year-old woman with NT at the 50th centile.18 The absence of a persuasive explanation for this association raised the possibility that assessment of the NB could be subjective and a function of the previous probability of trisomy 21 based upon other clinical factors.
What is the value of the NB in risk assessment of trisomy 21 in clinical practice? The complexity of NB assessment and the rigor required to maintain the skills, together with the potential for a subjective assessment, are limitations for the implementation of NB as a 1-step risk assessment procedure performed at the time of NT measurement. Therefore, it is unlikely that assessment of the fetal NB would be a
Ville universal risk assessment tool. On the other hand, we believe that the characteristics of the test make it an excellent candidate for contingency assessment for trisomy 21 in early pregnancy. Why? The term ‘‘contingency screening’’ refers to a program in which first-trimester risk assessment is complemented with a second test. The subsequent test could be a second trimester ultrasound, maternal serum markers, or other approaches. It is clear that imaging of the NB is unlikely to be part of the initial assessment. However, the test has the characteristics to be a second line screening that can be performed in early pregnancy. Indeed, the combination of NT, maternal age, and serum biochemistry can be used to classify the population into high, intermediate, and low risk. The intermediate risk group can then be studied with the NB. This program yields comparable results to those of an integrated screening, which include tests in the second trimester. The main advantage is that risk assessment is completed earlier in pregnancy. Fetal NB assessment would only need to be offered to 10% to 25% of the entire population participating in risk assessment (depending on the cut-off chosen to define those with intermediate risks).22 A similar approach has been proposed in the US for women at intermediate risk in the second trimester.23 Using this approach, even a high false-positive rate for the fetal NB in the intermediate risk group would not jeopardize the performance of the risk assessment program for the entire population. This is 1 of the main contributions of the study by Cicero et al, which is reported in this issue of the Journal. They propose that first trimester assessment be performed with combined NT and MSM at 11 to 14 weeks, and then offer fetal NB to the 10% of the population with an intermediate risk defined as ranging between 1/100 and 1/1000.18 Allocation of resources for risk assessment for all pregnant women in the first trimester for trisomy 21 by combining NT and MSM is cost-effective when the expenditure of ultrasound can be met locally24 and can, therefore, be offered to all women as an integral part of prenatal care. The concept of specialized units, where a second level of screening can be performed either in the first or second trimester to derive a new integrated risk assessment, appears to be the way of the future. This approach would ensure respect of women’s autonomy by avoiding unnecessary invasive testing or the ethical issues related to nondisclosure of early results while waiting for a second test in the midtrimester in the context of sequential screening.
References 1. Cicero S, Curcio P, Papageorghiou A, Sonek J, Nicolaides KH. Absence of nasal bone in fetuses with trisomy 21 at 11-14 weeks of gestation: an observational study. Lancet 2001;358:1665-7.
Ville 2. Minderer S, Gloning KP, Henrich W, Stoger H. The nasal bone in fetuses with trisomy 21: sonographic versus pathomorphological findings. Ultrasound Obstet Gynecol 2003;22:16-21. 3. Otano L, Aiello H, Igarzabal L, Matayoshi T, Gadow EC. Association between first trimester absence of fetal nasal bone on ultrasound and Down syndrome. Prenat Diagn 2002;22:930-2. 4. Orlandi F, Bilardo CM, Campogrande M, Krantz D, Hallahan T, Rossi C, et al. Measurement of nasal bone length at 11-14 weeks of pregnancy and its potential role in Down syndrome risk assessment. Ultrasound Obstet Gynecol 2003;22:36-9. 5. Viora E, Masturzo B, Errange G, Sciarrone A, Bastonero S, Campogrande M. Ultrasound evaluation of fetal nasal bone at 11 to 14 weeks in a consecutive series of 1906 fetuses. Prenat Diagn 2003;23:784-7. 6. Cicero S, Rembouskos G, Vandecruys H, Hogg M, Nicolaides KH. Likelihood ratio for trisomy 21 in fetuses with absent nasal bone at the 11-14-week scan. Ultrasound Obstet Gynecol 2004;23:218-23. 7. Larose C, Massoc P, Hillion Y, Bernard JP, Ville Y. Comparison of fetal nasal bone assessment by ultrasound at 11-14 weeks and by postmortem X-ray in trisomy 21: a prospective observational study. Ultrasound Obstet Gynecol 2003;22:27-30. 8. Zoppi MA, Ibba RM, Axiana C, Floris M, Manca F, Monni G. Absence of fetal nasal bone and aneuploidies at first trimester nuchal translucency screening in unselected pregnancies. Prenat Diagn 2003;23:496-500. 9. Malone FD, Ball RH, Nyberg DA, Comstock CH, Saade G, Berkowitz RL, et al. FASTER Research Consortium. First-trimester nasal bone evaluation for aneuploidy in the general population. Obstet Gynecol 2004;104:1222-8. 10. Goncalves LF, Espinoza J, Lee W, Romero R. Should the frontal bone be visualized in midline sagittal views of the facial profile to assess the fetal nasal bones during the first trimester? Ultrasound Obstet Gynecol 2005;25:90-4. 11. Lee W, DeVore GR, Comstock CH, Kalache KD, McNie B, Chaiworapongsa T, et al. Nasal bone evaluation in fetuses with Down syndrome during the second and third trimesters of pregnancy. J Ultrasound Med 2003;22:55-60. 12. Goncalves LF, Espinoza J, Lee W, Schoen ML, Devers P, Mazor M, et al. Phenotypic characteristics of absent and hypoplastic nasal bones in fetuses with Down syndrome: description by 3-dimensional ultrasonography and clinical significance. J Ultrasound Med 2004;23:1619-27.
3 13. Benoit B, Chaoui R. Three-dimensional ultrasound with maximal mode rendering: a novel technique for the diagnosis of bilateral or unilateral absence or hypoplasia of nasal bones in second-trimester screening for Down syndrome. Ultrasound Obstet Gynecol 2005; 25:19-24. 14. Peralta CF, Falcon O, Wegrzyn P, Faro C, Nicolaides KH. Assessment of the gap between the fetal nasal bones at 11 to 13 C 6 weeks of gestation by three-dimensional ultrasound. Ultrasound Obstet Gynecol 2005;25:464-7. 15. Sonek JD. Nasal bone evaluation with ultrasonography: a marker for fetal aneuploidy. Ultrasound Obstet Gynecol 2003;22:11-5. 16. Cicero S, Rembouskos G, Vandecruys H, Hogg M, Nicolaides KH. Likelihood ratio for Trisomy 21 in fetuses with absent nasal bone at the 11-14 weeks scan. Ultrasound Obstet Gynecol 2004; 23:218-23. 17. Cicero S, Dezerega V, Andrade E, Scheier M, Nicolaides KH. Learning curve for sonographic examination of the fetal nasal bone at 11-14 weeks. Ultrasound Obstet Gynecol 2003;22:135-7. 18. Cicero S, Avgidou K, Rembouskos G, Kagan KO, Nicolaides KH. Nasal bone in first-trimester screening for trisomy 21. Am J Obstet Gynecol 2006; in press. 19. Senat MV, Bernard JP, Boulvain M, Ville Y. Intra- and interoperator variability in fetal nasal bone assessment at 11-14 weeks of gestation. Ultrasound Obstet Gynecol 2003;22:138-41. 20. Cicero S, Sonek J, McKenna D, Croom C, Johnson L, Nicolaides KH. Nasal bone hypoplasia in fetuses with trisomy 21. Ultrasound Obstet Gynecol 2003;21:15-8. 21. Cicero S, Spencer K, Avgidou K, Faiola S, Nicolaides KH. Maternal serum biochemistry at 11-13(C6) weeks in relation to the presence or absence of the fetal nasal bone on ultrasonography in chromosomally abnormal fetuses: an updated analysis of integrated ultrasound and biochemical screening. Prenat Diagn 2005;25:977-83. 22. Wright D, Bradbury I, Benn P, Cuckle H, Ritchie K. Contingent screening for Down syndrome is an efficient alternative to nondisclosure sequential screening. Prenat Diagn 2004;24:762-6. 23. DeVore GR, Romero R. Genetic sonography: an option for women of advanced maternal age with negative triple-marker maternal serum screening results. J Ultrasound Med 2003;22:1191-9. 24. Odibo AO, Stamilio DM, Nelson DB, Sehdev HM, Macones GA. A cost-effectiveness analysis of prenatal screening strategies for Down syndrome. Obstet Gynecol 2005;106:562-8.