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Obstetrics & Gynecology 2002;100:648-654
© 2002 by The American College of Obstetricians and Gynecologists
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ORIGINAL RESEARCH

Measurement of Nuchal Translucency as a Single Strategy in Trisomy 21 Screening: Should We Use Any Other Marker?

Carmina Comas, PhD, Margarita Torrents, MD, Ana Muñoz, MD, Eugenia Antolín, PhD, Francesc Figueras, PhD and Mónica Echevarría, MD

From the Fetal Medicine Unit, Department of Obstetrics and Gynecology, Institut Universitari Dexeus, Barcelona, Spain.

Address reprint requests to: Carmina Comas, Departamento de Obstetricia y Ginecología, Institut Universitari Dexeus, Paseo Bonanova 67, Barcelona 08017, Spain; E-mail: carcom{at}iudexeus.uab.es.


   ABSTRACT
TOP
ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
OBJECTIVE: To evaluate the role of nuchal translucency thickness as a single marker in screening for trisomy 21 at 10–16 weeks’ gestation.

METHODS: From December 1996 to October 2001, nuchal translucency was measured in 11,281 consecutive early second trimester fetuses referred to our unit for prenatal care and delivery. Scans were performed by eight experienced ultrasonographers, under strict methodological criteria.

RESULTS: Chromosomal abnormalities were found in 118 cases (52 trisomy 21). Using nuchal translucency greater than the 95th centile as a cut-off, the overall detection rate was 71.2% with a specificity of 95.4%, and a positive predictive value of 14%. In the trisomy 21 selected group, detection rate, specificity, and positive predictive value for nuchal translucency were 92.3%, 95.4%, and 8.5%, respectively. The detection rate of trisomy 21 reached 100% when nuchal translucency was measured between 10 and 14 weeks’ gestation, maintaining the same specificity.

CONCLUSION: Early second trimester nuchal translucency measurement can achieve prenatal detection rates of trisomy 21 greater than 95% with a 5% false-positive rate. With a detection rate so high, the benefits of using additional markers may be less than previously considered. Although maternal age, other sonographic or Doppler markers, and maternal serum biochemistry might play a role in prenatal strategies to detect fetal chromosomal abnormalities, the high detection rate of trisomy 21 fetuses using nuchal translucency as a single parameter suggests that early nuchal translucency measurement between 10 and 14 weeks’ gestation can be a simple screening strategy for this condition.

Down syndrome is the most common cause of mental retardation of genetic origin, and many parents consider prenatal diagnosis of the condition desirable to have the option of terminating an affected pregnancy. Increased fetal nuchal translucency seems to be a well-established ultrasonographic marker for fetal aneuploidy screening, particularly when it is measured during the early mid-trimester of pregnancy.1–4 Therefore, nuchal translucency measurement is now widely used in many countries as a screening tool for Down syndrome. Maternal age, several sonographic and Doppler parameters, and maternal serum biochemistry have been included in fetal aneuploidy screening programs to improve the rates of detection. The aim of this study was to evaluate the role of nuchal translucency as a single marker in screening for trisomy 21 during the early second trimester of pregnancy, and whether a multiparametric strategy would improve the rates of detection. This study in a larger population confirms the preliminary results that have already been published by this group.5,6


   MATERIALS AND METHODS
TOP
ABSTRACT
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
From December 1996 to October 2001, ultrasound examinations were prospectively carried out on 11,281 consecutive first and early second trimester fetuses referred to our unit (private tertiary-level center) for prenatal care and delivery, without previous knowledge of the fetal karyotype. There were no previous selection criteria. Scans were performed transvaginally using a 6.5-MHz probe (at 10–13 weeks) and transabdominally with a 3.5-MHz probe (at 14–16 weeks) with a Toshiba ultrasound system (Toshiba SSH-140A, Toshiba Co., Tokyo, Japan). Gestational age was calculated from the last menstrual period and confirmed by measuring the crown–rump length (before the 12th week of gestation) or biparietal diameter and femur length. Ultrasound was always performed before biochemical screening or invasive procedures, and the sonographers were blinded to biochemical screening or karyotyping results. Informed consent was obtained from each patient, and the study was approved by our ethics committees.

Nuchal translucency was measured in a sagittal section of the fetus as the maximum thickness of the subcutaneous translucency between the skin and the soft tissue overlying the cervical spine.1 Calliper measurements were corrected to 0.1 mm. Ultrasound examinations were performed by eight experienced ultrasonographers, following strict methodological criteria (well-trained experienced operators, our own nomograms, rigorous audit).

Fetal karyotyping was performed in cases of advanced maternal age, family history of aneuploidy, and parental anxiety. Additionally, after the first investigation, invasive testing was indicated when biochemical screening for Down syndrome identified a risk greater than 1/270 or ultrasound anomalies were found (including malformations or nuchal translucency greater than the 95th centile). Chorionic villus sampling was performed transcervically at 10–13 weeks’ gestation, and amniocentesis was performed transabdominally at 14–16 weeks. Amniotic fluid was processed using the "in situ" method7 and chorionic villi were processed by the semidirect method.8 Postnatal follow-up confirming normal outcome and excluding trisomies was obtained after delivery in our unit or by phone interview.

All statistical analyses were performed with the SPSS 10.0 for Windows statistical software (SPSS Inc., Chicago, IL). Mean values and 95% confidence intervals (CI) for each parameter were established for each gestational week. Reference intervals were calculated using a centile method, excluding chromosomal abnormalities and fetal malformations detected by ultrasound. Significance level was set at P < .05. Proportions were compared using the {chi}2 test with Yates correction or the Fisher exact test when appropiate. Standard statistical analysis was used to evaluate the detection rate, specificity, positive predictive value, and negative predictive value of each parameter as a marker for chromosomal abnormalities. The odds ratio (OR) and the corresponding 95% CI were computed to provide a measure of strength.


   RESULTS
TOP
ABSTRACT
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
The mean maternal age was 32 years (range 14–49 years) (standard deviation [SD] 3.9). Seventy five percent of the women were younger than 35. Gestational age ranged from 10 to 16 weeks, and 66.8% were scanned between the 10th and the 13th week. A total of 118 chromosomal abnormalities were found, including trisomy 21 (n = 52), trisomy 18 (n = 15), trisomy 13 (n = 5), Turner syndrome (n = 11), Klinefelter syndrome (n = 5), triploidy (n = 3), and others (n = 27). Epidemiological data related to maternal age and gestational age in the overall population and in the chromosomally abnormal groups are described in Table 1Go. The incidence of chromosomal abnormalities was 1.1%, 0.8% in women younger than 35 (65/8458) and 1.9% in women older than 35 years (53/2823). The incidence of chromosomal abnormalities was 0.3% (34/10,682) when nuchal translucency measured less than the 95th centile, 14% (84/599) when nuchal translucency measured above the 95th centile, and 34.9% (66/189) when nuchal translucency measured above the 99th centile. In those cases in which fetal karyotyping was not performed, perinatal follow-up confirming normal outcome (referring to trisomy) was available in 98% of the cases.


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  		Table 1. Epidemiological Data Related to Maternal Age and Gestational Age in the Overall Population and the Chromosomally Abnormal Groups
 
Values for gestational age (in complete weeks by ultrasonography) were measured in 10,900 chromosomally normal fetuses (Table 2Go). Table 3Go shows the distribution of chromosomal abnormalities according to gestational age and nuchal translucency, using the 95th centile as a cut-off. At the same 5% false-positive rate, the detection rate was 92% for trisomy 21, 80% for trisomies 13 and 18, 82% for Turner syndrome, 67% for Klinefelter syndrome, 20% for triploidy, and 30% for other chromosomal abnormalities. We have included a table of the actual number of patients according to karyotype and nuchal translucency value (Table 4Go). Table 5Go summarizes the effectiveness of nuchal translucency as a marker for chromosomal abnormalities as a whole, using the 95th and 99th centiles as a cut-off. The detection rate, specificity, positive predictive value, negative predictive value, and OR (95% CI) for chromosomal abnormalities are shown. Results are displayed for the overall group and then broken down according to maternal age (younger than 35 years or 35 years and older), gestational age (10–13 weeks or 14–16 weeks), and type of chromosomal abnormality (main autosomal trisomies—trisomies 21, 18, and 13 or other abnormalities). Using nuchal translucency greater than the 95th centile as a cut-off, the overall detection rate was 71.2%, for a specificity of 95.4%, positive predictive value of 14%, negative predictive value of 99.7%, and OR of 51 (95% CI 34, 77). Nuchal translucency detection rate was significantly greater (P < .05) in the early gestational period (79.8%) and for the prediction of autosomal trisomies (90.3%). Using nuchal translucency greater than the 99th centile as a cut-off, the overall detection rate was 55.9%, for a specificity of 98.9%, positive predictive value of 34.9%, negative predictive value of 99.5%, and OR of 115 (95% CI 77, 172). The nuchal translucency detection rate was also better in the early gestational period (60.7%). The prediction for autosomal trisomies was better than for the overal chromosomal abnormality (73.6%), this difference being statistically significant (P < .05). The OR and the corresponding 95% CI were calculated and were all significant, being higher in the earliest gestational age and for autosomal trisomies.


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  		Table 2. Nuchal Translucency Values
 

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  		Table 3. Distribution of Chromosomal Abnormalities According to Gestational Age and Nuchal Translucency
 

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  		Table 4. Actual Number of Patients According to Karyotype (Abnormal or Normal) and Nuchal Translucency Value (Abnormal or Normal)
 

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  		Table 5. Nuchal Translucency Effectiveness as a Single Marker of Chromosomal Abnormalities
 
In the trisomy 21–selected group (Table 6Go), detection rate, specificity, and positive predictive value for nuchal translucency were 92.3%, 95.4%, and 8.5%, respectively, using the 95th centile as a cut-off. At the same specificity, the detection rate rises to 100% when nuchal translucency is measured at the early gestational period (at 10–14 weeks’ gestation) but decreases to 56% at 15–16 weeks’ gestation.


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  		Table 6. Nuchal Translucency Effectiveness as a Single Marker of Trisomy 21
 

   DISCUSSION
TOP
ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Increased nuchal translucency seems to be a well-established sonographic marker for aneuploidy screening, particularly when it is measured at an early gestational age. However, studies of its efficacy have yielded widely conflicting results, with detection rates ranging from 30% to 90% at the same 5% false-positive rate. Interestingly, a review of the current literature pertaining to nuchal markers suggests that the greater the experience of the group in nuchal translucency measurement, the better the results for prediction of aneuploidies. Current widespread application of first-trimester ultrasonography has enabled accumulation of an increasing body of knowledge pertaining to early screening for fetal aneuploidy. Following the initial reports,1–3,9–14 including our own preliminary experience,5 recent studies of large populations of patients at both high or low risk for chromosomal abnormalities demonstrate that increased nuchal translucency between 10 and 16 weeks’ gestation by either transabdominal or transvaginal ultrasonography may serve as a screening tool for fetal aneuploidy.4,6,15–18

In our study, early second trimester nuchal translucency measurement can achieve prenatal detection rates of trisomy 21 in excess of 95% at a 5% false-positive rate. The overall detection rate in our center is considerably higher than in other studies. Several factors can contribute to this fact: First, the study is carried out in a single private tertiary-level ultrasound center, following strict methodological criteria in nuchal translucency measurements (well-trained experienced operators, our own nomograms established in a population of more than 10,000 chromosomally normal fetuses, optimal repeatibility). Second, the timing of measurements was optimal in most cases (67% of patients were scanned at 10–13 weeks’ gestation). Finally, the distribution of chromosomal abnormalities in this study was such that 72/118 cases were common autosomal trisomies. Interestingly, the performance of this screening test is significantly better in the early gestational period and when predicting autosomal trisomies, particularly trisomy 21. We emphasize that, at the same 5% false-positive rate, the detection rate for trisomy 21 rises to 100% when nuchal translucency is measured at the early gestational period (at 10–14 weeks’ gestation) but decreases to 56% at 15 and 16 weeks’ gestation. In other studies including different gestational periods, detection rates were similar, and the contribution of nuchal markers decreased as the gestational age increased.13,19,20 Our results are consistent with the suggested transient appearance of nuchal translucency, which constitutes the main reason for selecting this particular gestational period for screening purposes. The pattern of chromosomal defects associated with increased nuchal translucency is similar to that observed in other studies,1,14 which confirms the value of this marker in the screening of the most common chromosomal anomalies, particularly trisomy 21.

Obviously, this screening test is more accurate when performed by experienced operators following strict methodological criteria and when measured at early second trimester. Methodological aspects related to training must be seriously considered in nuchal translucency implementation programs, to validate this strategy as a standard method in routine clinical practice. As with any new technology, it is essential that those undertaking the 10–16-week scan are adequately trained and that those results are subject to rigorous audit. Concerning the optimal gestational period, it is important to move screening strategies to earlier gestational ages because they have better performance during this period, and there are obvious advantages of an earlier prenatal diagnosis.

Two main questions remain to be answered concerning the issue of early prenatal screening of aneuploidies. First, what is the cost-effectiveness of adding other markers, such as maternal serum biochemistry or other sonographic and Doppler parameters? Second, what is the cost-effectiveness of a sequential approach combining first-trimester sonographic parameters and second-trimester biochemistry, knowing that first-trimester screening reduces the prevalence and the predictive value of maternal serum screening?21,22

Fetal nuchal translucency thickness at 10–14-week scan has been combined with maternal age to provide an effective method of screening for trisomy 21, achieving a detection rate about 70–80% at a 5% false-positive rate.1–3 When maternal serum biochemistry is also taken into account, the detection rate may rise to 90%.15 Recently, Doppler parameters have been suggested to improve the test performance in fetal aneuploidy screening. Increased impedance to flow in the umbilical artery,23–27 abnormal fetal heart rate,28–30 and abnormal ductus venosus flow31–35 have been described as potential markers of chromosomal abnormalities, although with variable results in the literature. But this prospective study in an unselected population demonstrates that a single simple standarized strategy, the nuchal translucency measurement, might achieve at least the same effectiveness. With such a high detection rate, the benefits of other additional markers may be less than previously thought.

On the other hand, a new proposed "integrated" approach using a panel of first- and second-trimester markers suggests that further improvement in the screening performance is possible, achieving a detection rate of 94% at a 5% false-positive rate.4,36–38 The sequential use of modalities with intermediate disclosure can be more practical but will generate a higher false-positive rate. Moreover, complex statistical modeling is needed to predict screening detection and false-positive rates for policies using different marker combinations and screening modalities, once we have demonstrated that they are statistically independent. Although better performance can be achieved by adding other independent markers or using a sequential first- and second-trimester policy, the high detection rate of trisomy 21 fetuses by using nuchal translucency as a single strategy suggests that early nuchal translucency measurement at 10–14 weeks’ gestation can be a simple screening strategy to detect this condition. Combined strategies might be useful when nuchal translucency measurement can not be implemented properly, when there are no economic restrictions in the screening policy, or in selected high-risk groups.

Although there is debate on issues involving the choice between first and second trimester, biochemistry or sonographic parameters, single or combined strategies, research or standard of care, we can state that nuchal translucency is the most effective single screening test for trisomy 21. Early second trimester nuchal translucency measurement can achieve prenatal detection rates of Down syndrome in excess of 95% at a 5% false-positive rate. No other screening test can detect such a proportion of affected pregnancies with such a low false-positive rate. If current trends continue, it is likely that the early scan for nuchal translucency measurement will become a routine component of antenatal care. Moreover, increased nuchal translucency can also identify a high proportion of other chromosomal abnormalities and is associated with major heart defects, a wide range of skeletal dysplasias, and genetic syndromes. Other benefits of the early scan include early diagnosis of major fetal defects and the detection of multiple pregnancies, as well as reliable identification of chorionicity. Therefore, it is imperative to standarize the implementation of nuchal translucency programs, the best cost-effective screening strategy for Down syndrome.


   Footnotes
 
The authors would like to thank the ultrasonographers M. Cararach and E. Scazzocchio, who also performed the ultrasound examinations reported in this study, Dr. J.C. Surís for his assistance in the statistical analysis, and Dr. Del Campo for reviewing the manuscript.

PII S0029-7844(02)02145-2

Received January 22, 2002. Received in revised form April 25, 2002. Accepted May 16, 2002.


   REFERENCES
TOP
ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
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6. Comas C, Antolín E, Torrents M, Muñoz A, Figueras F, Echevarría M, et al. Early screening for chromosomal abnormalities: New strategies combining biochemical, sonographic and Doppler parameters. Prenat Neonat Med 2001;6:95–102.

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12. Pandya PP, Altman D, Brizot ML, Pettersen H, Nicolaides KH. Repeatability of measurement of fetal nuchal translucency thickness. Ultrasound Obstet Gynecol 1995;5: 337–40.

13. Brambati B, Cislaghi C, Tului L, Alberti E, Amidani M, Colombo U, et al. First-trimester Down’s syndrome screening using nuchal translucency: A prospective study in patients undergoing chorionic villus sampling. Ultrasound Obstet Gynecol 1995;5:9–14.[Medline]

14. Ville Y, Lalondrelle C, Doumerc S, Daffos F, Frydman R, Oury JF, et al. First-trimester diagnosis of nuchal anomalies: Significance and fetal outcome. Ultrasound Obstet Gynecol 1992;2:314–6.[Medline]

15. Spencer K, Spencer CE, Power M, Moakes A, Nicolaides KH. One stop clinic for assessment of risk for fetal anomalies: A report of the first year of prospective screening for chromosomal abnormalities in the fisrt trimester. Br J Obstet Gynaecol 2000;107:1271–5.

16. Zoppi MA, Ibba RM, Putzolu M, Floris M, Monni G. Assessment of risk for chromosomal abnormalities at 10–14 weeks of gestation by nuchal translucency and maternal age in 5210 fetuses at a single centre. Fetal Diagn Ther 2000;15:170–3.[Medline]

17. Thilaganathan B, Sairam S, Michailidis G, Wathen NC. First trimester nuchal translucency: Effective routine screening for Down syndrome. Br J Radiol 1999;72: 946–8.[Abstract]

18. Sherer DM, Manning FA. First-trimester nuchal translucency screening for fetal aneuploidy. Am J Perinatol 1999; 16:103–20.[Medline]

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21. Michailidis GD, Spencer K, Economides DL. The use of nuchal translucency measurement and second trimester biochemical markers in screening for Down’s syndrome. Br J Obstet Gynaecol 2001;108:1047–52.

22. Schuchter K, Hafner E, Stangl G, Ogris E, Philipp K. Sequential screening for trisomy 21 by nuchal translucency measurement in the first trimester and maternal serum biochemistry in the second trimester in a low-risk population. Ultrasound Obstet Gynecol 2001;18:23–5.[Medline]

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29. Hyett JA, Noble PL, Snijders RJM, Montenegro N, Nicolaides KH. Fetal heart rate in trisomy 21 and other chromosomal abnormalities at 10–14 weeks of gestation. Ultrasound Obstet Gynecol 1996;7:239–44.[Medline]

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