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Obstetrics & Gynecology 2004;104:1229-1233
© 2004 by The American College of Obstetricians and Gynecologists
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ORIGINAL RESEARCH

The Association Between Fetal Nasal Bone Hypoplasia and Aneuploidy

Anthony O. Odibo, MD*, Harish M. Sehdev, MD{dagger}, Linda Dunn, MD{ddagger}, Raegan McDonald, MD§ and George A. Macones, MD, MSCE*

From the *University of Pennsylvania Medical Center, {dagger}Pennsylvania Hospital, and {ddagger}Chestnut Hill Hospital, Philadelphia, Pennsylvania; and §New York University Hospital, New York.

Address reprint requests to: Anthony Odibo, MD, Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, Hospital of the University of Pennsylvania, 3400 Spruce Street, 2000 Ravdin Courtyard, Philadelphia, PA 19104; e-mail: aodibo{at}mail.obgyn.upenn.edu.


   ABSTRACT
TOP
ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
OBJECTIVE: To determine the association between fetal nasal bone hypoplasia and aneuploidy in women undergoing prenatal diagnosis.

METHODS: A prospective cohort study involving women undergoing chorionic villus sampling and amniocentesis for an increased risk of aneuploidy. Fetal biometric and nasal bone measurements were obtained at the time of prenatal diagnosis and compared with karyotypes. Nasal bone hypoplasia was defined as nasal bone less than 2.5th percentile for the gestational age.

RESULTS: A total of 632 fetuses were evaluated. Twenty-nine (4.6%) had an aneuploidy (18 trisomy 21, 5 trisomy 18, 1 Turner's syndrome, one Marker chromosome 1, 2 sex chromosome anomalies, and 2 triploidy). Nasal bone measurements were documented in 29 aneuploid fetuses. The nasal bone was either absent or hypoplastic in 12 of 29 (41%) fetuses with aneuploidy and in 8 of 18 (44%) with trisomy 21. By using receiver operating characteristics curves, the optimal threshold of nasal bone hypoplasia associated with fetal aneuploidy was a biparietal diameter/nasal bone ratio of 11 or greater. The sensitivity, specificity, and positive and negative predictive values for the detection of fetal aneuploidy were 50%, 93%, 24%, and 98%, respectively.

CONCLUSION: Absent or hypoplastic nasal bone is a marker for fetal aneuploidy in a high-risk population. However, this marker needs to be evaluated by larger prospective studies in low-risk populations before adoption for clinical use.

LEVEL OF EVIDENCE: II-2

Many choices for screening for fetal aneuploidy are now available to women. These strategies include the use of maternal age, maternal serum markers, and ultrasonographic findings.1

Recent reports have suggested that an absent fetal nasal bone or nasal bone hypoplasia is a marker for aneuploidy.2 Cicero et al2 reported an absent nasal bone in 73% of fetuses with aneuploidy at the time of chorionic villus sampling. After their report, several studies in the first and second trimester have reported conflicting results on the association between nasal bone and fetal aneuploidy.3–12 In the recently completed FASTER trial, none of the fetuses with trisomy 21 had absent nasal bone in the first trimester. (Malone FD, Wald NJ, Canick JA. First- and Second-Trimester Evaluation of Risk [FASTER] Trial: Principle Results of the NICHD Multicentre Down Syndrome Screening Study [abstract]. Am J Obstet Gynecol 2003;189:S56). In addition, when an association between nasal bone hypoplasia and fetal aneuploidy has been reported, the authors have used several definitions of nasal bone hypoplasia. Other limitations of these reports include a skewed spectrum of diagnostic criteria, lack of clarity regarding inclusion criteria, and absence of statements about the frequency of other abnormal findings. Due to these conflicting definitions and results, we performed this study with the aim of evaluating the relationship between nasal bone length and fetal aneuploidy at the time of prenatal diagnosis in our population.


   MATERIALS AND METHODS
TOP
ABSTRACT
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
This is a prospective study including women referred to our units for prenatal diagnosis due to an increased risk for aneuploidy. The study was performed over a period of 18 months between November 2002 and May 2004. The prenatal diagnostic tests included a chorionic villus sampling (CVS) between 11 and 14 weeks or amniocentesis between 15 and 22 weeks. In women seen for an amniocentesis a detailed anatomic survey within the limits of the gestational age was performed. In those having a CVS, a fetal crown-rump length was determined and assessment of nuchal translucency was made. Nasal bone assessment was performed on all women attending for karyotyping except when this was impossible due to fetal position. Approval from the Institutional Review Board of all participating centers was obtained.

Fetal nasal bone was assessed as previously described by Sonek et al.3 Briefly, the facial profile of the fetus was obtained in the midsagittal plane and by rocking the transducer sideways. The angle of insonation was maintained at 45 or 135 degrees. The nasal bone is seen as a triangular echogenic structure in this view. All sonographic evaluations were performed by experienced American Registry of Diagnostic Medical Sonographers certified sonographers with training in first-trimester screening ultrasonography. We evaluated the following definitions of nasal bone hypoplasia for association with fetal aneuploidy: absent nasal bone; nasal bone below 2.5th or 5th percentile for gestational age using the chart by Sonek et al13; and a ratio of biparietal diameter to nasal bone length more than 9–12.10 Finally, a receiver operating characteristic curve was created to determine the optimal nasal bone threshold associated with fetal aneuploidy. The results of nasal bone evaluation were not used as an indication for prenatal diagnosis.

Statistical analysis was performed using {chi}2 test for categorical variables and student t test for continuous variables. The primary outcome was the association between nasal bone and fetal aneuploidy. All analysis was performed using STATA 8.0 (College Station, TX).


   RESULTS
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ABSTRACT
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
A total of 655 women received prenatal diagnosis during the study period. Nasal bone assessment was possible in 632 (96%) women. The maternal demographic characteristics, indications, and type of prenatal diagnostic tests are shown in Table 1. The majority of our patients were white, and the main indications for the procedure were advanced maternal age and abnormal multiple marker screening. Amniocentesis was the most common prenatal diagnostic test performed. There were 29 (4.6%) aneuploid fetuses. Table 2 depicts the types of fetal aneuploidy detected, and trisomy 21 was the most common type of aneuploidy detected.


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  		Table 1. Maternal Demographics and Indications for Prenatal Diagnosis

 

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  		Table 2. Types of Fetal Aneuploidy Seen in the Study Population

 

The mean maternal age ± standard deviation was 36.8 ± 5.4 years in those with an aneuploid fetus compared with 35.4 ± 4.5 years in the women with a euploid fetus (P = .17), and the mean gestational age of testing was 16.4 ± 2.9 weeks in the aneuploid fetuses compared with 16.7 ± 2.1 weeks in the euploid fetuses (P = .56). The mean nasal bone measurement in the aneuploid compared with the euploid fetuses was 3.1 ± 01.99 mm and 4.7 ± 2.7 mm, respectively (P = .04).

The efficiency of using various nasal bone criteria for the detection of all cases of aneuploidy and trisomy 21 is shown in Tables 3 and 4, respectively. Nasal bone absence was seen in 6 of 29 (21%) of all aneuploid fetuses and in 14 of 583 (2%) euploid fetuses. Of the cases with trisomy 21, 5 of 18 (28%) had an absent nasal bone. Using nasal bone less than the 2.5th percentile for gestational age as the criteria for hypoplasia, the sensitivity for detecting all aneuploid fetuses was 44% with a specificity of 91%. The use of biparietal diameter/nasal bone length ratio 9 or greater in the second trimester yielded the highest sensitivity for detecting all types of aneuploidy, 12 of 22 (54%) with a specificity of 71%. Similarly, the biparietal diameter/nasal bone length ratio 9 or greater had the highest sensitivity (53%) for detecting trisomy 21, with a specificity of 71% (Table 4). Figure 1 is the receiver operating characteristic curve using the various biparietal diameter/nasal bone ratios to detect trisomy 21. It shows that the optimal nasal bone threshold associated with trisomy 21 is a biparietal diameter/nasal bone length ratio of 11 or greater. The latter had a sensitivity of 50% and a false positive rate of 7% for detection of trisomy 21, likelihood ratio for a positive test of 7.1. The area under the receiver operating characteristic curve was 0.75.


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  		Table 3. The Efficiency of Detection of Fetal Aneuploidy by Nasal Bone Criteria

 

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  		Table 4. The Efficiency of Detection of Trisomy 21 by Nasal Bone Criteria

 


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  		Fig. 1. Receiver operating characteristic curve using biparietal diameter/nasal bone ratio to detect trisomy 21. Arrow corresponds to biparietal diameter/nasal bone 11 or greater. Area under the receiver operating characteristic curve = 0.75.

Odibo. Nasal Bone Hypoplasia and Fetal Aneuploidy. Obstet Gynecol 2004.

 

When stratified by the type of prenatal diagnostic test or first and second trimester, an absence of nasal bone was seen in 0 of 6 (0%) of aneuploid fetuses detected in the first trimester and in 6 of 23 (26%) of aneuploid fetuses diagnosed in the second trimester. The specificity of using an absent nasal bone as the screening criteria was 42 of 47 (97%) and 527 of 540 (98%) in the first and second trimesters, respectively. The one case of trisomy 21 seen in the first trimester had a normal nasal bone length. Nasal bone less than 2.5th percentile for the gestational age was seen in 0 of 6 (0%) of the first-trimester aneuploidy and in 12 of 23 (52%) of the second-trimester aneuploidy, with specificity of 97% and 91% respectively. Similar findings were seen with a nasal bone less than the 5th percentile with an associated reduction in second-trimester specificity to 88%. Of the 5 cases with trisomy 18, nasal bone was absent in 1 (20%), less than the 2.5th or 5th percentile in 2 of 5 (40%), and 3 of 5 (60%) had biparietal diameter/nasal bone ratios of 11 or more. The specificity for detection of trisomy 18 (not shown) using nasal bone was similar to those reported above for trisomy 21 and all aneuploidy.


   DISCUSSION
TOP
ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Our study confirms an association between nasal bone hypoplasia and fetal aneuploidy in high-risk women. However, this association was modest. When used as a screening test in this high-risk population, the positive predictive values and likelihood ratios from a positive test were poor. In a low-risk population with a lower prevalence of fetal aneuploidy, the efficacy of using nasal bone hypoplasia as a screening test may be even lower. These limitations would suggest that the association between nasal bone and aneuploidy is not as robust to be an isolated screening test. A normal nasal bone length was, however, universally associated with high negative predictive values. This could prove useful in helping women avoid invasive testing (that is, when nasal bone is present with no other sonographic marker for aneuploidy). The area under the receiver operating characteristic curve was 0.75. An ideal screening test should have an area under the receiver operating characteristic curve (AUC) above 0.7. Another interpretation of the AUC is: Given 2 new cases, the biparietal diameter/nasal bone ratio gives you a 75% chance of predicting correctly which one will have aneuploidy. However, the ideal cutoff point is always a trade-off between the sensitivity of the test and the specificity, without really changing the accuracy. In the context of screening for aneuploidy, the efficacy of the biparietal diameter/nasal bone ratio is comparable to some of our current markers. It is superior to maternal age and close to the sensitivity of the triple screen (60%). The current study aimed to evaluate nasal bone as an isolated marker. It is possible that when combined with other markers for aneuploidy (for example, a genetic ultrasonogram), the sensitivity for detecting aneuploidy may improve.

We also found a biparietal diameter/nasal bone ratio of 11 or greater to be the optimal threshold definition of nasal bone hypoplasia associated with fetal aneuploidy. With the sensitivity of 50% and a false positive rate of 7%, there will be 1 false positive for every 7 true positive cases identified. When compared with previous studies evaluating the association between nasal bone and aneuploidy, our study showed a relatively lower sensitivity and specificity (Table 5). The sensitivity from our study is similar to that reported by Vintzeleos et al9 but our specificity is lower. Differences in our patient population and inclusion criteria may account for the lower test characteristics. These differences suggest a need for further studies to evaluate the role of nasal bone length as a screening tool for aneuploidy. We also sought to determine if the use of an absolute threshold of nasal bone length such a 2.5 mm as proposed by Cicero et al12 or 4 mm (the mean nasal bone for our study population) had a better discriminatory value as a screening for aneuploidy in the second trimester. Using these threshold values was not associated with improved sensitivity for trisomy 21 detection compared with the biparietal diameter/nasal bone ratio of 11 or greater. Due to the small number of women who had CVS, we are unable to comment on the role of nasal bone as a first-trimester screen.


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  		Table 5. Review of Selected Studies on the Association of Nasal Bone and Trisomy 21

 

The biologic explanation for nasal bone hypoplasia in the presence of trisomy 21 or aneuploidy is still unknown. Both post mortem radiologic and histopathologic evidence exist to support this association between nasal bone and trisomy 21.14–15 Stempfle et al14 reported absence of nasal bone ossification in 23% of trisomic fetuses compared with none of the euploid fetuses examined using postmortem radiographs. In contrast, Minderer et al15 found only 2 of 17 cases of trisomy 21 examined by postmortem histology to lack ossification centers. The latter authors compared these results with prenatal ultrasound findings in these fetuses and confirmed that some cases in which the nasal bone was considered absent on ultrasound examination, the histologic finding was hypoplastic ossification instead. This illustrates the need for attention to the details of methodology of nasal bone evaluation during prenatal ultrasonography. Our sonographers were all trained in the technique of nasal bone measurement; therefore, the modest prediction of aneuploidy from this study is not secondary to poor technique.

Our study has several limitations. These include a relatively small number of fetuses with aneuploidy and enrollment of high-risk women only. We chose to evaluate the role of nasal bone in this high-risk population before undertaking a more detailed assessment in the general population. In addition, the small number of women receiving CVS precludes conclusions regarding nasal bone performance in the first trimester. The latter reflects the low demand for CVS in our population, similar to most centers in the United States. Therefore, the conclusions from this study may be applicable to second-trimester ultrasonography only. Our study population was mostly white women, and the small size makes it difficult to comment on the influence of race on the utility of nasal bone.

In conclusion, nasal bone hypoplasia is associated with trisomy 21 and other fetal chromosomal abnormalities. The use of a second-trimester biparietal diameter/nasal bone ratio of 11 or more was the optimal threshold definition of nasal bone hypoplasia associated fetal aneuploidy. Larger studies are needed in low-risk populations to determine the role of nasal bone hypoplasia either as an isolated marker or in combination with other sonographic markers.


   Footnotes
 
Presented at the Annual Meeting of American Institute for Ultrasound in Medicine, Phoenix, AZ, June 19–22, 2004.

Received July 12, 2004. Received in revised form August 20, 2004. Accepted September 1, 2004.

doi:10.1097/01.AOG.0000148848.49752.37


   REFERENCES
TOP
ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
1. Mennuti MT, Driscoll DA. Screening for Down's syndrome: too many choices? N Engl J Med 2003;349:1471–3.[Free Full Text]

2. Cicero S, Curcio P, Papageorghiou A, Sonek J, Nicolaides K. Absence of nasal bone in fetuses with trisomy 21 at 11–14 weeks gestation: an observational study. Lancet 2001;358:1665–7.[Medline]

3. Sonek JD, Nicolaides KH. Prenatal ultrasonographic diagnosis of nasal bone abnormalities in three fetuses with Down syndrome. Am J Obstet Gynecol 2002;186:139–41.[Medline]

4. 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.[Medline]

5. Zoppi MA, Ibba RM, Axiana C, Floris M, Manca F, Monni G. Absence of fetal nasal bone and aneuploidies at first-trimester nuchal translucency in unselected pregnancies. Prenat Diagn 2003;23:496–500.[Medline]

6. 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.[Medline]

7. Viora E, Masturzo B, Errante G, Sciarrone A, Bastonero S, Campogrande M. Ultrasound evaluation of fetal nasal bone at 11–14 weeks in a consecutive series of 1906 fetuses. Prenat Diagn 2003;23:784–7.[Medline]

8. Cicero S, Longo D, Rembouskos G, Sacchini C, Nicolaides KH. Absent nasal bone at 11–14 weeks of gestation and chromosomal defects. Ultrasound Obstet Gynecol 2003;22:31–5.[Medline]

9. Vintzileos A, Walters C, Yeo L. Absent nasal bone in the prenatal detection of trisomy 21 in a high-risk population. Obstet Gynecol 2003;101:905–8.[Abstract/Free Full Text]

10. Bromley B, Lieberman E, Shipp TD, Benacerraf B. Fetal nasal bone length: a marker for Down syndrome in the second trimester. J Ultrasound Med 2002;21:1387–94.[Abstract/Free Full Text]

11. Bunduki V, Ruano R, Miguelez J, Yoshizaki CT, Kahhale S, Zugaib M. Fetal nasal bone length: reference range and clinical application in ultrasound screening for trisomy 21. Ultrasound Obstet Gynecol 2003;21:156–60.[Medline]

12. Cicero S, Sonek JD, Mckenna DS, Croom CS, Johnson L, Nicolaides KH. Nasal bone hypoplasia in trisomy 21 at 15–22 weeks’ gestation. Ultrasound Obstet Gynecol 2003;21:15–8.[Medline]

13. Sonek JD, McKenna D, Webb D, Croom C, Nicolaides K. Nasal bone length throughout gestation: normal ranges based on 3537 fetal ultrasound measurements. Ultrasound Obstet Gynecol 2003;21:152–5.[Medline]

14. Stempfle N, Huten Y, Fredouille C, Brisse H, Nessmenn C. Skeletal abnormalities in fetuses with Down's syndrome: a radiographic post-mortem study. Pediatr Radiol 1999;29:682–8.[Medline]

15. 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.[Medline]




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