Thickness of Nuchal Translucency and Chromosomal Aneuploidy

THICKNESS OF NUCHAL TRANSLUCENCY

AND CHROMOSOMAL ANEUPLOIDY

Video clip of increased Nuchal Translucency - Trisomy 21

Thickness of nuchal translucency (mm)
Maternal age related risks for trisomies 21, 18, and 13.
3 mm 4 mm 5 mm > 6 mm		Increases 4-fold (3,4) Increases 21-fold (3,4) Increases 26-fold (3,4) Increases 41-fold (3,4)

Studies of nuchal translucency ultrasound in an unselected prenatal population
316,311 patients screened by NT measurement in the first trimester. A total of 1177 fetuses with Down syndrome were ascertained in this population,
Ref	Number of fetuses	Down syndrome
Ref	Number of fetuses	Prevalence of Down syndrome / 1000 ascertained pregnancies	Sensitivity (%)	FPR %	PPV %	LR (+)	LR (−)
1	537	13	2/7 (29)	6.4	5.6	5	0.8
2	6939	0.9	4/6 (67)	0.8	6.7	83	0.3
3	4233	1.7	3/7 (43)	1.7	4.1	25	0.6
4	2256	3.5	5/8 (63)	1	17.9	63	0.4
5	3550	3.1	10/11 (91)	2.6	9.9	35	0.1
6	96,127	3.4	268/326 (82)	8	3.4	10	0.2
7	1473	6.1	6/9 (67)	1.8	18.2	37	0.3
8	1467	8.9	8/13 (62)	6.7	7.5	9	0.4
9	424	16.5	7/7 (100)	1.7	50	59	—
10	6443	3.6	13/23 (57)	0.3	37.1	188	0.4
11	4523	2.7	10/12 (83)	4.9	4.3	17	0.2
12	9802	2.1	16/21 (76)	4.7	3.3	16	0.3
13	5809	5.7	24/33 (73)	5	7.6	15	0.3
14	1000	8	6/8 (75)	6.2	8.8	12	0.3
15	1602	3.1	3/5 (60)	11.6	1.6	5	0.5
16	9342	2	11/19 (58)	2.3	5	25	0.4
17	4130	2.9	9/12 (75)	4.9	4.3	15	0.3
18	7447	3.1	19/23 (83)	4.5	5.4	18	0.2
19	21959	9.6	174/210 (83)	8.9	8.2	9	0.2
20	10,157	6.3	58/64 (91)	9.6	5.7	9	0.1
21	2557	3.9	7/10 (70)	6.5	4	11	0.3
22	6841	2.5	17/17 (100)	4.3	5.5	23	—
23	4939	2.8	8/14 (57)	4.9	3.2	12	0.5
24	1152	12.2	9/14 (64)	4.2	15.8	15	0.4
25	6234	3.4	13/21 (62)	2.8	7	22	0.4
26	17,229	2.6	20/37 (54)	5	2.3	11	0.5
27	16,237	2.2	24/35 (69)	5	2.9	14	0.3
28	14,383	5.7	64/82 (79)	5	8.3	16	0.2
29	7536	5	38/38 (100)	5	9.4	20	—
30	39,983	2.1	54/85 (63)	5	2.6	13	0.4
TOTAL	316,311	3.7	910/1,177 (77.3)	5.9	4.7	13.1	0.24
TOTAL			(95% CI: 75–80)	(5.8–6)	(4.5–4.8)	(12.7–13.5)	(0.22–0.27)

Pooled 95% confidence intervals given in parentheses at bottom of table. FPR, Falsepositive rate; LR (+), likelihood ratio for Down syndrome given positive result; LR (−), likelihood ratio for Down syndrome given negative result; MoM, multiples of median; PPV, positive predictive valuez.
Prevalence of Down syndrome - 3.7 per 1000 pregnancies. In 11 of the 30 studies included in the above table, the prevalence of Down syndrome was 5 per 1000 or greater, suggesting that these studies were not representative of the general obstetric population. Using data from all 30 studies, NT screening had an overall sensitivity for Down syndrome of 77% with a 6% false-positive rate. The odds of a positive screen result being a true positive for Down syndrome were approximately 5%. The data from these studies suggest that an abnormal NT measurement is 13 times more likely to be present in cases of Down syndrome, compared with when the fetus does not have this condition. Conversely, a normal NT measurement is about one quarter as likely in unaffected cases.

Nuchal translucency thickness of ³ 3mm was found in 86.1% of trisomic fetuses versus 4.5% of chromosomally normal fetuses (31).
Nuchal translucency thickness of ³ 3mm was associated with a 12-fold increase in maternal age related risk for fetal aneuploidy 3(1).
Incidence of chromosomal defects according to fetal nuchal translucency (32) – 96127 singleton pregnancies:

Nuchal translucency 3.4 mm or less (95086 fetuses) – Chromosomal defects in 0.33%.
Nuchal translucency 3.5 - 4.4 mm (568 fetuses) - Chromosomal defects in 21%.
Nuchal translucency 4.5 - 5.4 mm (207 fetuses) - Chromosomal defects in 33%.
Nuchal translucency 5.4 - 6.4 mm (97 fetuses) - Chromosomal defects in 50%.
Nuchal translucency of 6.5 mm or higher (166 fetuses) - Chromosomal defects in 65.5%.

The Fetal Medicine Foundation study described previously observed that NT-based screening may identify other aneuploidies beside Down syndrome. Based on prenatal diagnosis and neonatal ascertainment, it observed detection rates of:

· 81% for trisomy 18,

· 80% for Turner's syndrome,

· 63% for triploidy.

· Cases that would be expected to spontaneously demise were not included in the analysis (35). Because the true prevalence of these conditions in the first trimester is uncertain, and most affected fetuses spontaneously die in utero, true detection rates for these cases are difficult to calculate. Based on the frequency of these aneuploidies observed in newborns, it is estimated that approximately 80% of these cases result in spontaneous abortion in the absence of screening (36). It is possible that NT-based screening may preferentially identify those pregnancies with the highest likelihood of intrauterine death (37). It is a matter of debate whether a screening method that identifies such pregnancies holds any advantage for the screened population.

REFERENCES

Kornman LH, Morssink LP, Beekhuis JR, De Wolf BT, Heringa MP, Mantingh A. Nuchal translucency cannot be used as a screening test for chromosomal abnormalities in the first trimester of pregnancy in a routine ultrasound practice. Prenat Diagn 1996;16:797-805
Taipale P, Hiilesmaa V, Salonen R, Ylostalo P. Increased nuchal translucency as a marker for fetal chromosomal defects. N Engl J Med 1997;337:1654-8
Hafner E, Schuchter K, Liebhart E, Philipp K. Results of routine fetal nuchal translucency measurement at weeks 10–13 in 4233 unselected pregnant women. Prenat Diagn 1998;18:29-34
Economides DL, Whitlow BJ, Kadir R, Lazanakis M, Verdin SM. First trimester sonographic detection of chromosomal abnormalities in an unselected population. BJOG 1998;105:58-62.
Theodoropoulos P, Lolis D, Papageorgiou C, Papaioannou S, Plachouras N, Makrydimas G. Evaluation of first-trimester screening by fetal nuchal translucency and maternal age. Prenatal Diagnosis 1998;18:133-7.
Snijders RJ, 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;352:343-56
Pajkrt E, van Lith JM, Mol BW, Bilardo CM. Screening for Down's syndrome by fetal nuchal translucency measurement in a general obstetric population. Ultrasound Obstet Gynecol 1998;12:163-9.
De Biasio P, Siccardi M, Volpe G, Famularo L, Santi F, Canini S. First-trimester screening for Down syndrome using nuchal translucency measurement with free β–hCG and PAPP-A between 10 and 13 weeks of pregnancy – the combined test. Prenat Diagn 1999;19:360-3.
Quispe J, Almandoz A, de Quiroga M, Isabel M. Traslucencia nucal fetal, un marcador de alteraciones cromosomicas en el primer trimester. Ginecol Obstet Mex 1999;45:183-6.
Whitlow BJ, Chatzipapas IK, Lazanakis ML, Kadir RA, Economides DL. The value of sonography in early pregnancy for the detection of fetal abnormalities in an unselected population. BJOG 1999;106:929-36.
Schwarzler P, Carbalho JS, Senat MV, Masroor T, Campbell S, Ville Y. Screening for fetal aneuploidies and fetal cardiac abnormalities by nuchal translucency thickness measurement at 10–14 weeks of gestation as part of routine antenatal care in an unselected population. BJOG 1999;106:1029-34.
Thilaganathan B, Sairam S, Michailidis G, Wathen NC. First trimester nuchal translucency: effective routine screening for Down's syndrome. Br J Radiol 1999;72:946-8.
Krantz DA, Hallahan TW, Orlandi F, Buchanan P, Larsen JW, Macro JN. First-trimester Down syndrome screening using dried blood biochemistry and nuchal translucency. Obstet Gynecol 2000;96:207-13.
O'Callaghan SP, Giles WB, Raymond SP, McDougall V, Morris K, Boyd J. First trimester ultrasound with nuchal translucency measurement for Down syndrome risk estimation using software developed by the Fetal Medicine Foundation, United Kingdom – the first 2000 examinations in Newcastle, New South Wales, Australia. Aust N Z J Obstet Gynaecol 2000;40:292-5.
Niemimaa M, Suonpaa M, Perheentupa A, Seppala M, Heinonen S, Laitinen P, et al. Evaluation of first trimester maternal serum and ultrasound screening for Down's syndrome in Eastern and Northern Finland. Eur J Hum Genet 2001;9:404-8.
Schuchter K, Hafner E, Stangl G, Ogris E, Philipp K. Sequential screening for trisomy 21 by nuchal translucency measurement in the first trimester and serum biochemistry in the second trimester in a low-risk population. Ultrasound Obstet Gynecol 2001;18:23-5.
Audibert F, Dommergues M, Bennattar C, Taieb J, Thalabard JC, Frydman R. Screening for Down syndrome using first-trimester ultrasound and second-trimester maternal serum markers in a low-risk population: a prospective longitudinal study. Ultrasound Obstet Gynecol 2001;18:26-31
Michailidis GF, Spencer K, Economides DL. The use of nuchal translucency measurement and second trimester biochemical markers in screening for Down's syndrome. BJOG 2001;108:1047-52
Gasiorek-Wiens A, Tercanli S, Kozlowski P, Kossakiewicz A, Minderer S, Meyberg H, et al. Screening for trisomy 21 by fetal nuchal translucency and maternal age: a multicenter project in [26].
Zoppi MA, Ibba RM, Floris M, Monni G. Fetal nuchal translucency screening in 12,496 pregnancies in Sardinia. Ultrasound Obstet Gynecol 2001;18:649-51.
Brizot ML, Carvalho MH, Liao AW, Reis NS, Armbruster-Moraes E, Zugaib M. First-trimester screening for chromosomal abnormalities by fetal nuchal translucency in a Brazilian population. Ultrasound Obstet Gynecol 2001;18:652-5.
Wayda K, Kereszturi A, Orvos H, Horvath E, Pal A, Kovacs L, et al. Four years experience of first-trimester nuchal translucency screening for fetal aneuploidies with increasing regional availability. Acta Obstet Gynecol Scand 2001;80:1104-9.
Schuchter K, Hafner E, Stangl G, Metzenbauer M, Hofinger D, Philipp K. The first trimester ‘combined test’ for the detection of Down syndrome pregnancies in 4939 unselected pregnancies. Prenat Diagn 2002;22:211-5.
Murta CG, Franca LC. Medida da translucencia nucal no rastreamento de anomalies cromossomicas. Rev Bras Ginecol Obstet 2002;24:167-73.
Rozenberg P, Malagrida L, Cuckle H, Durand-Zaleski I, Nisand I, Audibert F, et al. Down's syndrome screening with nuchal translucency at 12 + 0 – 14 + 0 weeks and maternal serum markers at 14 + 1 – 17 + 0 weeks: a prospective study. Hum Reprod 2002;17:1093-8.
Crossley JA, Aitken DA, Cameron AD, McBride E, Connor JM. Combined ultrasound and biochemical screening for Down's syndrome in the first trimester: a Scottish multicentre study. BJOG 2002;109:667-76.
Lam YH, Lee CP, Sin SY, Tang R, Wong HS, Wong SF, et al. Comparison and integration of first trimester nuchal translucency and second trimester maternal serum screening for fetal Down syndrome. Prenat Diagn 2002;22:730-5.
Bindra R, Heath V, Liao A, Spencer K, Nicolaides KH. One-stop clinic for assessment of risk for trisomy 21 at 11–14 weeks: a prospective study of 15,030 pregnancies. Ultrasound Obstet Gynecol 2002;20:219-25.
Comas C, Torrents M, Munoz A, Antolin E, Figueras F, Echevarria M. Measurement of nuchal translucency as a single strategy in trisomy 21 screening: should we use any other marker? Obstet Gynecol 2002;100:648-54.
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.
Nicolaides KH, Brizot ML, Snijders RJM. Fetal nuchal translucency; ultrasound screening for fetal trisomy in the first trimester of pregnancy. Br J Obstet Gynaecol 1994;101:782-786.
Snijders RJM, Noble P, Sebire N et.al. 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;351:343-346.
Panyada PP, Brizot ML, Snijders RJM. Fetal nuchal translucency thickness and risk for trisomies. Obstet Gynecol 1994;84:420-423.
Panyada PP, Kondylioa A, Hilbert L et.al. Chromosomal defects and outcome in 1015 fetuses with increased nuchal translucency. Ultrasound Obstet Gynecol 1995;5:15-19.
Snijders RJ, 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;352:343-56
Penn PA. Advances in prenatal screening for Down syndrome: II first trimester testing, integrated testing, and future directions. Clin Chim Acta 2002;324:1-11.
Pandya PP, Snijders RJ, Psara N, Hilbert L, Nicolaides KH. The prevalence of non-viable pregnancy at 10–13 weeks of gestation. Ultrasound Obstet Gynecol 1996;7:170-3.