The Institute for Advanced Medical Education is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.

The Institute for Advanced Medical Education designates this educational activity for a maximum of 1 AMA PRA Category 1 Credit(s) TM. Physicians should only claim credit commensurate with the extent of their participation in the activity.

These credits are accepted by the American Registry for Diagnostic Medical Sonography (ARDMS).

Faculty:
Lyndon M. Hill, MD
Professor Obstetrics and Gynecology
Medical Director Ultrasound
Magee Women's Hospital
Pittsburgh, PA

Course: First Trimester Screening For Chromosomal And Structural Malformations

Target Audience: Physicians, sonographers and others who perform and/or interpret obstetrical ultrasound.

System requirements: In order to complete this program you must have a computer with a recent version of Internet Explorer or Netscape, and a printer, which is configured to print from the browser.

For any questions or problems concerning this program or for problems related to the printing of the certificate please contact IAME at (914) 921-5700 or email us.

Estimated Time for Completion of tutorial: One hour
Date of Release and Review: April 7, 2006
Expiration Date: April 7, 2009

Disclosure: In compliance with the Essentials and Standards of the ACCME, the author of this CME tutorial is required to disclose any significant financial or other relationships they may have with the manufacturer(s) of any commercial product(s) or provider(s) of any commercial service(s) discussed in this program.

Dr. Lyndon Hill discloses no relevant financial relationships with commercial interests.

IAME discloses no relevant financial relationships with commercial interests. 

IAME Statement on Privacy and Confidentiality

First Trimester Screening For Chromosomal And Structural Malformations
Lyndon M. Hill, MD
Professor Obstetrics and Gynecology
Medical Director Ultrasound
Magee Women's Hospital
Pittsburgh, PA

(DIRECT TO QUIZ)

Objectives
After completing this course, the participant should be able:

• Describe the possible etiologies of a thickened nuchal translucency.
• Apply the NT measurement technique in the first trimester and recognize the effect of multiple gestation on this measurement.
• Improve outcomes in your practice through recognition of the prevalence of abnormalities in chromosomally normal fetuses with an increased NT

Introduction
An association between an abnormally thickened nuchal translucency (NT) and chromosomal abnormalities was first noted in the early 1990s1. However, the early studies reported widely discordant sensitivities for the detection of chromosomal malformations. These discrepancies were due to a lack of consistency between examiners with respect to:

1. Study group - low-risk versus high-risk
2. Gestational age at examination
3. Measurement technique
4. Cut-off for an abnormal nuchal translucency
5. Incorporation of serum markers into the evaluation
6. Level of sonographer training

Serum Analytes
First trimester serum analytes - free ß-hcg (HCG) and pregnancy - associated plasma protein (PAPP-A) - are currently utilized to screen for Down syndrome. HGC tends to be increased and PAPP-A decreased with Down syndrome. The detection rate for Down syndrome with the first trimester analytes alone is approximately 60% with a 5% false positive rate².

 Pathophysiology of a thickened nuchal translucency
A multitude of different structural anomalies and chromosomal abnormalities are associated with an increased NT. This suggests that there is more than one pathophysiologic mechanism associated with a thick NT. The possible etiologies that have been proposed to date, include3: 

1. Abnormal lymphatic drainage
2. Altered extracellular matrix
3. Abnormal cardiac structure and/or function
4. Venous congestion
5. Hypoproteinemia
6. Genetic causes of fetal anemia (e.g., alphathalassemia)

Since the thickness of the nuchal translucency increases with gestational age, utilization of a single cut-off would tend to increase the false negative rate at earlier gestational ages and increase the false positive rate later in the first trimester. Nuchal translucency measurements, therefore, evolved from a threshold value to multiples of the median that were utilized to modify the patient's age related risk of a karyotypic abnormality. Nuchal translucency measurements without combined serum screening has a low specificity and is, no longer recommended1 .

A combination of fetal nuchal translucency with maternal serum PAPP-A and ß-hCG has a detection rate of approximately 90% for trisomies 21, 18 and 13, Turner's syndrome and triploidy with a 5% false positive rate4 .

The resolution of a thickened NT as gestation advances is not indicative of a normal karyotype5 .

A 12 center North American study offered first trimester screening with NT, free ß-hCG and PAPP-A to patients with a singleton pregnancy between 74 and 97 days gestation based on the crown-rump length6 . 8,514 women were screened. 78.7% of trisomy 21 fetuses and 90.9% of fetuses with trisomy 18 were identified with a false positive rate of 5% and 2%, respectively. In contrast to prior studies, this investigation took into consideration differences in the rates of spontaneously aborted trisomy 21 fetuses at various gestational ages. The good performance of first trimester screening was not based on the identification of pregnancies that would have spontaneously aborted. The successful screening for trisomy 21 by fetal nuchal translucency utilizing the Fetal Medicine Foundation protocol has been confirmed in other countries7 , as well as in the United States6 .

Measurement Technique 
The Fetal Medicine Foundation has standardized NT measurement in the first trimester. The measurement is performed at a crown-rump length between 45 mm and 84 mm8 . Over 90% of exams are performed transabdominally; occasionally the transvaginal approach is required. The fetal head and chest should be enlarged to 75% of the screen. The fetus is imaged in a mid-sagittal plane with the head in a neutral position. The mean NT when the head is extended or flexed is 0.62 mm greater and 0.40 mm less, respectively, than an NT measured with the head in a neutral position9 .

The amnion should be distinguished from the fetal skin. The calipers are placed on the inner border of the nuchal translucency and perpendicular to the long axis of the fetal body. The largest of three measurements is reported (Fig. 1).

Figure 1 - Normal 1st trimester nuchal translucency (1.7 mm). To view an enlargement, click on the image.

The importance of image size was emphasized by Edwards et al10 - an increase in image magnification from 60% to 200% resulted in a 29% decrease in the NT measurement.

A nuchal cord is present in approximately 8% of 10-14 week fetuses. A nuchal cord will add 0.8 mm to the NT measurement. If a nuchal cord is suspected, color Doppler should be used to exclude this possibility before an NT measurement is obtained11 (Figs. 2, 3).

Figure 2 - 1st trimester fetus with the umbilical cord around the neck (arrow) affecting the nuchal translucency measurement.		Figure 3 - Transverse image of the fetus in figure 3. Power Doppler is used to show the cord around the neck.
To view an enlargement, click on the image.

Nuchal Translucency Screening in Multiple Gestations
In one study the nuchal translucency thickness was above the 95 th centile in 7.3% of twin fetuses, including 88% with trisomy 2112 . In chromosomally normal twins, the prevalence of an increased NT is higher in monochorionic (8.4%) versus dichorionic (5.4%) twins. It has been postulated that the increased false positive rate with monochorionic twins is due to a thickened NT being an early manifestation of a shared placental circulation, i.e. twin-to-twin transfusion syndrome.

Outcome in fetuses with normal chromosomes and a thick nuchal translucency 
As the NT increases in chromosomally normal fetuses, the risk of the following poor outcome variables also increases:

1. Miscarriage
2. Intrauterine death
3. Major structural defects
4. Postnatal demise

The chance of an adverse outcome with normal chromosomes and an NT of 3.5 - 4.4 mm, 4.5 - 5.4 mm (Fig. 4a), 5.5 - 6.4 mm and >= 6.5 mm (Fig. 4b) is 32%, 49%, 67% and 89%, respectively13 . The persistence of nuchal edema at a 20 week scan increases the likelihood of an adverse outcome by 9-fold overall13 .

Figure 4a		Figure 4b
Thick 1st trimester nuchal translucency: a) 4.9 mm; b) 9.0 mm.
To view an enlargement, click on the image.

The prevalence of major abnormalities in chromosomally normal fetuses increases from 2.5% with an NT between the 95 th and 99 th centile to 45% when the NT is >= 6.5 mm13, 14 . Numerous structural abnormalities have been associated with an increased NT. However, an association does not indicate that a true relationship exists between a thickened NT and a particular structural defect. The prevalence of congenital heart defects, diaphragmatic hernia, and fetal akinesia deformation sequence appears to be substantially higher in fetuses with a thickened NT than in the general population3 .

The list of structural abnormalities that have been associated with a thick first trimester NT continues to increase (Table I)3 . Since some of these abnormalities have subtle features, a completely normal second trimester ultrasound examination will reduce the risk of an underlying abnormality to approximately 2%, i.e. the normal background risk of a structural malformation3,15 .

Major Cardiac Defects 
In karyotypically normal fetuses with a thickened nuchal translucency, the prevalence of major cardiac defects increases exponentially with the thickness of the fetal NT. Atzei et al 16 reported a prevalence of major cardiac defects of 35.2/1,000, 64.4/1,000 and 126.7/1,000 with an NT of 3.5 - 4.4 mm, 4.5 - 5.4 mm and >= 5.5 mm, respectively.

In a meta-analysis of first trimester NT screening for major cardiac defects, Makrydimas et al17 found that the 99 th percentile for NT detected approximately 30% of congenital heart defects. The type of congenital heart defects reported include ventricular septal defects, tetrology of Fallot, atrioventricular canal defects, and complex cardiac abnormalties18 . Hence, in karyotypically normal fetuses with a thickened NT, a careful second trimester evaluation of cardiac anatomy should be performed.

Developmental Delay 
In chromosomally normal fetuses with NT >= 3.5 mm, some concern has been raised about a possible 2 - 4% risk of developmental problems in early childhood19 . When a cut-off of 4 mm is used, the risk of a significant neurologic handicap was 11.1%20 . The studies to date are flawed by: 1) variable NT measurements used to enter the study group; 2) limited sample size; 3) the use of a retrospective questionnaire rather than a neonatal examination; and 4) duration of follow up after delivery. Prospective long-term follow up of children with a thickened NT and normal chromosomes is, therefore, required.

Ductus Venosus 
An association has been established between absent or reversed flow in the ductus venosus and aneuploidy (Fig. 5). It has been hypothesized that the abnormal ductus venosus blood flow indicates either a defective atrial contraction or poor ventricular compliance. The finding of an abnormal ductus venosus pattern is, therefore, indirect evidence for cardiac failure as one possible etiologic mechanism of a thickened NT21 . In a highly selected at-risk population, Mavrides et al22 noted that an abnormal ductal pattern increased the risk of aneuploidy by 10-fold. By combining nuchal translucency serum analytes and abnormal ductal blood flow, a sensitivity of 90.5%23 to 94%22 has been achieved for the detection of trisomy 21. However, the prevalence of absent or reversed flow in normal pregnancies has not yet been ascertained. In addition, the overlapping of signals from adjoining vessels sometimes makes interpretation of the ductal waveform patterns difficult.

Figure 5a - transverse		Figure 5b - sagittal
Diastolic flow is present within the ductus venosus. To view an enlargement, click on the image.

Because of the specialized nature of this test, it has not yet gained wide acceptance. Its application my lie, not in screening, but as a second-tier test to reduce the false positive rate in patients considered at risk for a karyotypic abnormality based upon the nuchal translucency measurement and serum analytes. Matias nad Montenegro24 have calculated that this schema would detect about 85% of trisomy 21 pregnancies after invasive testing in < 0.5% of the population. Nicolaides et al25 reported a 90% detection rate for trisomy 21 with a 2% - 3% false positive rate using the same two-stage first trimester screen.

Nasal Bone Length 
The assessment of the nasal bone reduces the false positive rate of a first trimester genetic screen26 . Since the length of the nasal bone increases with advancing gestation, the false positive rate is higher at 11, in contrast to 13, weeks. Ethnicity may also play a role in the rate of an absent nasal bone27 . With a fixed 1/250 risk cut-off, Orlandi et al26 increased the detection rate of first trimester screening by including an assessment of the nasal bone from 87% to 90% with a reduction in the false positive rate from 4.3% to 2.5%.

In order to visualize the nasal bone between 11 and 13 weeks 6 days, a mid-sagittal view of the profile is required. With appropriate magnification only the head and upper chest should be on the image. When the correct view is obtained the skin line and underlying nasal bone are in parallel; the echogenic tip of the nose is also on the image27 (Fig. 6). Experienced sonographers generally require between 40 and 120 scans to become competent in looking for the first trimester nasal bone28 .

Figure 6- 1st trimester nasal bone (arrow). To view an enlargement, click on the image.

The success rate of obtaining a fetal profile between 11 and 14 weeks' gestation is between 75.9%29 and 98.9%27 . Maternal body mass index was found to significantly affect nasal bone imaging29 . The FASTER trial evaluated 6,324 first trimester patients for the presence or absence of the nasal bone and concluded that an evaluation of the nasal bone did not improve the detection rate of aneuploidy in the general population. Additional studies of a general population in which the nasal bone is assessed by appropriately trained sonographers is, therefore, required. The advantage of evaluating the nasal bone is in its reduction of the false positive rate. As a result, this examination may find a place as a second tier study in fetuses with a thick NT.

References

1. Malone FD, D'Alton ME. First-trimester sonographic screening for Down syndrome. Society for Maternal-Fetal Medicine. Obstet Gyecol 2003;102:1066-1079.
2. Haddow JE, Palomaki GE, Knight GJ, Williams J, Miller WA, Johnson A. Screening of maternal serum for fetal Down's syndrome in the first trimester. N Engl J Med 1998;338:955-961.
3. Souka AP, vonKaisenberg CS, Hyett JA, Sonek JD, Nicolaides KH. Increased nuchal translucency with normal karyotype. Am J Obstet Gynecol 2005;192:1005-1021.
4. Spencer K, Spencer CE, Power M, Dawson C, Nicolaides KH. Screening for chromosomal abnormalities in the first trimester using ultrasound and maternal serum biochemistry in a one-stop clinic: a review of three years prospective experience. Br J Obstet Gynaecol 2003;110:281-286.
5. Pandya PP, Snijders RJM, Johnson S, Nicolaides KH. Natural history of trisomy 21 fetuses with increased nuchal translucency thickness. Ultrasound Obstet Gynecol 1995;5:381-383.
6. Wapner R, Thom E, Simpson SL, Pergament E, Silver R et al. First-trimester screening for trisomies 21 and 18. N Engl J Med 2003;349:1405-1413.
7. Gasiorek-Wiens A, Tercanli S, Lozlowski P, Lossakiewicz A, Minderer S et al. Screening for trisomy 21 by fetal nuchal translucency and maternal age: a multicenter project in Germany , Austria and Switzerland . Ultrasound Obstet Gynecol 2001;18:645-648.
8. Nicolaides KH. Nuchal translucency and other first-trimester sonographic markers of chromosomal abnormalities. Am J Obstet Gynecol 2004;191:45-67.
9. Whitlow BJ, Chatzipapas IK, Economides DL. The effect of fetal neck position on nuchal translucency measurement. Br J Obstet Gynaecol 1998;105:872-876.
10. Edwards A, Mulvey S, Wallace EM. The effect of image size on nuchal translucency measurement. Prenat Diagn 2003;23:284-286.
11. Schaefer M, Laurichesse-Delmas H, Ville Y. The effect of nuchal cord on nuchal translucency measurement at 10-14 weeks. Ultrasound Obstet Gynecol 1998;11:271-273.
12. Sebire NJ , Snijders R, Hughes K, Sepulveda W, Nicolaides KH. Screening for trisomy 21 in twin pregnancies by maternal age and fetal nuchal translucency thickness at 10-14 weeks of gestation. Br J Obstet Gynaecol 1996;103:999-1003.
13. Souka AP, Krampl E, Bakalis S, Heath V, Nicolaides KH. Outcome of pregnancy in chromosomally normal fetuses with increased nuchal translucency in the first trimester. Ultrasound Obstet Gynecol 2001;18:9-17.
14. Souka AP, Snidjers RJM, Novakov A, Soares W, Nicolaides KH. Defects and syndromes in chromosomally normal fetuses with increased nuchal translucency at 10-14 weeks of gestation. Ultrasound Obstet Gynecol 1998;11:391-400.
15. Hyett J. Increased nuchal translucency in fetuses with a normal karyotype. Prenat Diagn 2002;22:864-868.
16. Atzei A, Gajewska K, Huggon IC, Allan L, Nicolaides KH. Relationship between nuchal translucency thickness and prevalence of major cardiac defects in fetuses with normal karyotype. Ultrasound Obstet Gynecol 2005;26:154-157.
17. Makrydimas G, Sotiriadis A, Ioannidis PA. Screening performance of first-trimester nuchal translucency for major cardiac defects: a meta-analysis. Am J Obstet Gynecol 2003;189:1330-1335.
18. Bahado-Singh RO, Wapner R, Thom E, Zachery J, Platt L, Mahoney MJ et al. Elevated first-trimester nuchal translucency increases the risk of congenital heart defects. Am J Obstet Gynecol 2005;192:1357-1361.
19. Ville Y. Nuchal translucency in the first trimester of pregnancy: ten years on and still a pain in the neck? (Opinion). Ultrasound Obstet Gynecol 2001;18:5-8.
20. Senat MV, De Keersmaecker B, Audibert F, Montcharmont G, Frydmen R, Ville Y. Pregnancy outcome in fetuses with increased nuchal translucency and normal karyotype. Prenat Diagn 2002;22:345-349.
21. Montenegro N, Matias A, Areias JC, Castedo S, Barros H. Increased fetal nuchal translucency: possible involvement of early cardiac failure. Ultrasound Obstet Gyncol 1997;10:265-268.
22. Mavrides E, Sainam S, Hollis B, Thilaganathan B. Screening for aneuploidy in the first trimester by assessment of blood flow in the ductus venosus. Br J Obstet Gynaecol 2002;109:1015-1019.
23. Matias A, Gomes C, Flack N, Montenegro N, Nicolaides KH. Screening for chromosomal abnormalities at 10-14 weeks: the role of ductus venosus blood flow. Ultrasound Obstet Gynecol 1998;12:380-384.
24. Matias A, Montenegro N. Ductus venosus and prenatal diagnosis. Ultrasound Rev Obstet Gynecol 2003;3:19-25.
25. Nicolaides KH, Spencer K, Avgidou K, Faiola S, Falcon O. Multicenter study of first-trimester screening for trisomy 21 in 75,821 pregnancies: results and estimation of the potential impact of individual risk-oriented two-stage first-trimester screening. Ultrasound Obstet Gynecol 2005;25:221-226.
26. Orlandi F, Rossi C, Orlandi E, Jakil MC, Hallahan TW, Macri VJ, Krantz DA. First trimester screening for trisomy-21 using s simplified method to assess the presence or absence of the fetal nasal bone. Am J Obstet Gynecol 2005;192:1107-1111.
27. 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. Ultarsound Obstet Gynecol 2004;23:218-223.
28. Kanellopoulos V, Katsetos C, Economides DL. Examination of fetal nasal bone and repeatability of measurement in early pregnancy. Ultrasound Obstet Gynecol 2003;22:131-134.
29. Malone FD, Ball RH, Nyberg DA, Comstock CH, Saade G et al. First-trimester nasal bone evaluation for aneuploidy in the general population. Obstet Gynecol 2004;104:1222-1228.

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