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Screening performance of first-trimester nuchal translucency for major cardiac defects: a meta-analysis
Screening performance of first-trimester nuchal translucency for major cardiac defects: A meta-analysis George Makrydimas, MD,a Alexandros Sotiriadis, MD,a and John P. A. Ioannidis, MDb,c Ioannina, Greece, and Boston, Mass OBJECTIVE: The purpose of this study was to evaluate the screening performance of increased first-trimester nuchal translucency for the detection of major congenital heart defects. STUDY DESIGN: A meta-analysis based on MEDLINE and EMBASE searches (up to June 2002) that assessed the diagnostic performance of increased nuchal translucency for congenital heart defect detection. Weighted sensitivity and specificity estimates (random effects) and summary receiver-operating characteristic curves were obtained. RESULTS: Eight independent studies with 58,492 pregnant women were analyzed. There was significant heterogeneity among the studies. Nuchal translucency above the 99th percentile had a sensitivity of 31% and specificity of 98.7% (random effects calculations), with a positive likelihood ratio of 24. Summary receiveroperating characteristic estimates were consistent with these values. The ability of nuchal translucency measurements above this threshold to detect cardiac malformations varied nonsignificantly (P = .64) for different congenital heart defects types (sensitivity range, 25%-55%). CONCLUSION: Nuchal translucency screening is a modestly efficient strategy for congenital heart defect detection; the use of the 99th percentile threshold may capture approximately 30% of congenital heart defects. (Am J Obstet Gynecol 2003;189:1330-5.)
Key words: Nuchal translucency, cardiac defect, meta-analysis
Abnormalities of the heart and the great vessels, found in 2 to 8 of every 1000 pregnancies, are the most common congenital defects and they are responsible for approximately 10% of neonatal deaths and 45% of infant deaths in the form of birth defects.1,2 Routine second-trimester ultrasound scans with a four-chamber view (4CV) have unpredictable performance for detecting congenital heart defects (CHDs),3-5 although detailed cardiac scans that are performed at specialist centers can detect most of these lesions.6 At present, referral to such specialist centers is based on maternal history of diabetes mellitus or exposure to teratogens, a family history of CHD, obvious abnormalities on ultrasound scan with a 4CV, or noncardiac defects that are known to be associated with CHD, such as diaphragmatic hernia or exomphalos. However, only 10% of the children who are born with CHD have such an identifiable risk factor.6 A promising, simple screening test for CHD is the measurement of fetal nuchal translucency (NT) at 11 to From the Department of Obstetrics and Gynaecology,a and the Clinical Trials and Evidence-Based Medicine Unit, Department of Hygiene and Epidemiology,b University of Ioannina School of Medicine, and the Division of Clinical Care Research, Tufts–New England Medical Center.c Received for publication December 4, 2002; revised April 15, 2003; accepted May 16, 2003. Reprint requests: John P.A. Ioannidis, MD, Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina 45110, Greece. E-mail: [email protected] Ó 2003, Mosby, Inc. All rights reserved. 0002-9378/2003 $30.00 + 0 doi:10.1067/S0002-9378(03)00645-8
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14 weeks of gestation. Fetal NT, in combination with maternal age and maternal serum markers, can detect approximately 90% of fetuses with trisomy 21 and other major chromosomal defects.7 In addition, several studies have shown that there is a strong association between increased NT and major cardiac defects, which suggests that this test could be used concomitantly for both chromosomal and cardiac screening. The largest study has shown a sensitivity of 56% for the detection of the severe cardiac defects among chromosomally normal fetuses.8 Other studies, however, have failed to reproduce these results, and there remains a considerable uncertainty about the exact diagnostic performance of NT for CHD. Even studies with several thousand pregnancies have relatively few CHD cases, and their results may be inconclusive when seen in isolation. It is unknown whether differences between studies may have been due to chance or may reflect genuine diversity or bias. To address these issues and to establish whether there is a role for NT measurements in screening for CHD, we performed a comprehensive meta-analysis of the available evidence.
Methods Search strategy and eligibility criteria. Studies were retrieved from MEDLINE and EMBASE searches (1985 to June 2002) with the keywords (fetal) nuchal translucency, cardiac defect, and cardiac anomalies. References of retrieved articles were also screened. All studies were compared
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carefully to assure that we avoided using duplicate reports of the same subjects. We also communicated with primary investigators and field experts to obtain additional data that were not reported clearly in published reports and to clarify study design issues. Studies were eligible if they described the presence or not of clinically significant cardiac defects in chromosomally normal fetuses that were split according to normal versus increased NT measurements in the first trimester. We accepted the definition of cardiac defects as provided by each study but generally excluded insignificant and transient cardiac defects that resolved spontaneously on subsequent examinations. Cardiac defects could have been diagnosed by fetal echocardiography, postmortem examination (in cases of fetal death), or postnatal clinical examination. In the case of data duplication or overlap, only the largest or most recent study with available data was included. Some variability across studies in the definition of significant cardiac defects and in the follow-up period of ascertainment may be unavoidable. The effect of such variability on the observed prevalence of cardiac defects is probably small compared with the effect of the background risk of the study population. Data extraction. Information was extracted on study population characteristics, age of pregnancy at which sonography was performed, inclusion and exclusion criteria, study design, outcome assessment and potential selection and verification bias, and 2 3 2 tables that classified the presence or not of cardiac defects according to different NT thresholds. Two investigators performed independent data extraction. Discrepancies were evaluated jointly with a third investigator, and consensus was reached for all data. Evaluation of diagnostic performance. The main parameters of diagnostic performance included sensitivity and specificity of increased NT for cardiac defects. Increased NT may be defined with different thresholds. Therefore, we agreed to examine two separate analyses. The first analysis (low-threshold analysis) included thresholds that corresponded to the 95th percentile (2.2-2.8 mm), depending on gestational age.9 If such data were not available in a study, we accepted a threshold of 2.5 mm, or, if this was also unavailable, 3 mm. The second analysis (high-threshold analysis) included thresholds that corresponded to the 99th percentile or, alternatively, to 3.5 mm. The two thresholds are practically equivalent, regardless of gestational age.9 If such data were not available in a study, we accepted data on the threshold closest to 3.5 mm, within the range of 3 to 5 mm. Meta-analysis. Analyses were performed separately for the high-threshold and low-threshold data. We used two methods for assessing the overall diagnostic performance of increased NT: independently combined sensitivity and specificity values and summary receiver-operating characteristic (SROC) curve analysis.
Heterogeneity of sensitivity and specificity estimates across studies was evaluated with the v2 test or Fisher exact test, as appropriate. We used both fixed and random effects models to estimate a weighted sensitivity and specificity across studies. The fixed effects model weighs each study by the inverse of its variance. Random effects incorporate both within-study and between-study variation. Random effects tend to provide wider confidence intervals and are generally preferable. The derived weighted estimates were used to estimate the positive likelihood ratio (LR+, Sensitivity/[1 Specificity]) and the negative likelihood ratio (LR, [1 Sensitivity]/Specificity). LR values are always larger than 0. A diagnostic test has no discriminating performance when the LR values are 1. The discriminating performance is better, the higher the LR+ and the smaller the LR. Independent weighted estimation of sensitivity and specificity may sometimes underestimate both, because these measures are interdependent. The SROC method accounts for this interdependence by fitting a curve that best describes the tradeoff between sensitivity and specificity across studies.10 The regression is D = a + bS, where D is the difference of the logits of the true positive rate (sensitivity) and false-positive rate (1 specificity) and S is the sum of these logits. Both weighted and unweighted SROC methods were used. Independent weighted estimates and SROC results were compared for consistency. We also estimated separately the sensitivity for different types of CHD and evaluated by the Fisher exact test whether the observed differences across CHD types were overall statistically significant. Positive predictive value. The positive predictive value of increased NT is the probability that a fetus has a cardiac defect when NT is increased (ie, P[Cardiac defect/ Increased NT]). This probability depends on the overall background prevalence P (previous probability) of cardiac defects in the study population (ie, P[Cardiac defect/Increased NT] = [P(LR+)/(1 P)]/ [1 + (P[LR+]/[1 P])]). Prevalence and LR+ values were derived from the meta-analysis. Analyses were conducted in SPSS (SPSS, Inc, Chicago, Ill), Meta-test ( Joseph Lau, Boston, Mass), and StatXact (Cytel, Inc, Boston, Mass). Results Eligible studies. The literature search identified 48 items. Sixteen were excluded on closer examination of the abstract. Of the items that were retrieved in full-text, 8 items actually did not provide the NT data, and 13 items included only cases with increased NT. Eleven reports were considered potentially eligible for the meta-analysis.8,11-20 One report was excluded13 because its study population had been described in more detail elsewhere.11 Another report was excluded12 because it was a subset of another larger study.8 Finally, we excluded one
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Table I. Descriptive characteristics of the eligible studies No. excluded Study
Gestational age (wk)
Study design
No. included
Chromosomal abnormalities
Other reasons*
Bilardo et al11 Hafner et al14 Josefsson et al15 Hyett et al8 Schwa¨rzler et al16 Michailidis and Economides18 Mavrides et al19 Orvos et al20
10-14 10-13 CRL, 31-84 mm 10-14 10-14 12-13 10-14 10-13
Prospective Prospective Prospective Retrospective Prospective Retrospective Prospective Retrospective
1,590 4,214 1,460 29,154 4,474 6,606 7,339 3,655
50 19 0 323 23 44 NDy 15
223 138 ND 1685 26 850 ND 3002
ND, Not defined. *Includes losses to follow-up and cases of fetal demise or termination of pregnancy without ascertainment of cardiac status. yAlthough the number is not stated, all chromosomal abnormalities have been excluded.
Table II. Included studies: Thresholds and results Study
NT threshold
Bilardo et al11 $3 mm Hafner et al14 $2.5 mm Josefsson et al15 $2.5 mm $3.5 mm >95th Hyett et al8 percentile >3.5 mm $2.5 mm Schwa¨rzler et al16 Michailidis >95th and percentile Economides18 >99th percentile Mavrides et al19 $2.5 mm $3.5 mm $3 mm Orvos et al20
True False False True positive negative positive negative 2 4 5 0 28
2 10 8 13 22
45 59 129 6 1794
1541 4141 1318 1441 27310
20 1
30 8
295 121
28809 4344
4
7
231
6364
3
8
70
6525
4 3 18
22 23 17
254 57 83
7059 7256 3537
study17 that described referred fetuses with suspicion for cardiac disease (based on either increased NT or other findings), but with no information available on the total number of fetuses who had NT evaluations (the population basis for the referred cases [Dr John Simpson, personal communication, June 2002]). Therefore, eight independent studies were considered in the meta-analysis. Study characteristics. In all studies (Table I), NT was measured consistently at a gestational age of 10 to 14 weeks (corresponding to a crown-rump length of 38-84 mm) as the maximal sonolucent distance between the inner border of the fetal skin and the outer border of the cervical spine in a mid sagittal section of the fetus. The eligible group excludes cases of chromosomal abnormalities in all studies; chromosomal abnormalities were detected in 0% to 2.6% of each study population. There were some differences across studies concerning the diagnostic documentation for CHD. Prenatal sonographic evaluation and/or postnatal clinical assessment had been performed routinely in all studies, but the percentage of non evaluated cases varied across studies.
Exclusions for reasons other than the presence of chromosomal abnormalities accounted for 0.6% to 13.6% of the original study population who had NT evaluations in five studies8,11,14,16,18 and were likely to be also very limited in another prospective study,15 although no exact numbers were provided. Orvos et al20 examined only the cases that were followed until delivery or fetal death specifically at the study center; thus, 45% of cases who had NT measurements were not included in the data (Dr Janos Szabo, personal communication, June 2002). Finally, in another study, no information was provided on these exclusions (Table I).19 All eight studies provided data on low thresholds, and six studies provided data on high thresholds (Table II).8,11,15,18-20 In total, the eight studies included 58,492 chromosomally normal fetuses, of which 162 fetuses had a diagnosis of cardiac defect. Data synthesis. The prevalence of CHD differed significantly among the included studies (P < .01). The prevalence was 0.2% to 0.4% in six studies and 0.9% to 1.0% in two studies. Across all eight eligible studies, cardiac defects were seen in 162 of 58,492 examined cases (0.28%). When limited to the six studies that provided data for the high-threshold analysis, the prevalence was similarly 139 of 49,804 cases (0.28%). There was significant between-study heterogeneity across studies in the specificity and sensitivity estimates; therefore, random effects are preferable over fixed-effects estimates. By random effects calculations, the independently weighted sensitivity and specificity were 37% (95% CI, 25%-51%) and 96.6% (95% CI, 95.1%-97.6%) for the low-threshold analysis and 31% (95% CI, 18%-49%) and 98.7% (95% CI, 98.1%-99.2%) for the high-threshold analysis. SROC analyses suggested similar diagnostic performance (Figure, A and B), and all the studies operated diagnostically in close proximity to the drawn SROC curves. Weighted and unweighted SROC curves were practically coinciding (Figure). Excluding the largest study,8 the sensitivity estimates were 33% (95% CI, 22%47%) and 27% (95% CI, 11%-53%) by random effects for
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the low- and high-threshold analysis, respectively, and the SROC curve was not shifted. The sensitivity of NT measurements varied somehow across different CHD types (Tables III and IV), and variability seemed more prominent in the low-threshold analyses. Nevertheless, even for lesions for which the 4CV has very poor screening performance (eg, tetralogy of Fallot, transposition of great vessels, coarctation of the aorta, and aortic stenosis), sensitivity varied between 25% and 50% with the high threshold (Table III). Movement to the low threshold did not seem to improve the detection rate for these difficult-to-diagnose CHD types (Table IV). The differences between various types of lesions could have been due to chance, given the small numbers of cases in each type of CHD, but modest differences cannot be excluded, especially for the lowthreshold analyses (exact P = .64 for high-threshold, P = .08 for low-threshold). The random effects estimates corresponded to an LR+ of 11 and an LR of 0.65 for the low-threshold analysis and an LR+ of 24 and an LR of 0.70 for the highthreshold analysis. The LR+ values suggest that the positive predictive value in a population with 0.28% prevalence of CHD is approximately 3% and 6%, respectively, for low- and high-threshold calculations.
Comment The findings of this meta-analysis demonstrate a significant association between increased NT and CHD. Despite the strong statistical significance, the clinical efficiency for the detection of cardiac lesions is modest. Approximately 30% of fetuses with major cardiac defects may be identified by specialist echocardiography in chromosomally normal fetuses with NT above the 99th percentile. Most fetuses with increased NT have a normal heart: 1 in 33 fetuses who are referred for detailed cardiac echocardiography because of NT above the 95th percentile would have a major cardiac defect detected. If the 99th percentile were used for detailed cardiac screening, 1 in 16 referred cases would have a major cardiac defect detected. We recorded no obvious strong verification bias in the analyzed studies, and the numbers of losses to follow-up and of dead fetuses with insufficient documentation of cardiac status were not large enough to change these conclusions. Nevertheless, some verification bias may be unavoidable, because increased NT may have led to a more intensive investigation for CHD. Such bias may be expected to be stronger for NT measurements above the high threshold, and this may offer an explanation for the apparently small increase in sensitivity when moving from the 99th to the 95th percentiles. However, verification bias might have been more prominent for cases with fewer severe cardiac defects that would not have come to medical attention, even after birth. Variable postnatal follow-up
Figure. SROC analyses for the ‘‘low-threshold’’ (A) and ‘‘highthreshold’’ (B) analyses. Each study is shown by a circle that denotes its true-positive rate (sensitivity) and false-positive rate (1 Specificity). Also shown are the SROC curves for weighted (thick line) and unweighted (thin line) analyses. The crosses denote the independently weighted sensitivity and specificity estimates across all studies by random effects estimation; the shaded boxes show the corresponding 95% CIs.
in these studies may also cause variable verification bias. However, cases that were diagnosed in late postnatal follow-up contribute less to death and morbidity than the major CHD that were considered in this meta-analysis.
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Table III. Proportion of various types of congenital heart disease with NT measurements above the selected high-threshold in each study
Study Bilardo et al11 Hyett et al8 Michailidis and Economides18 Mavrides et al19 Orvos et al20 TOTAL
Atrial septal defect or ventricular septal defect (n/N)
Fallot (n/N)
Coarctation of the aorta or aortic stenosis (n/N)
Hypoplastic left heart (n/N)
Transposition of the great arteries (n/N)
Other (n/N)
Multiple anomalies (n/N)
0/0 1/8 1/2
0/1 2/9 0/2
0/0 3/3 0/2
2/2 1/2 0/2
0/0 2/5 0/1
0/1 3/6 2/2
0/0 8/17 0/0
0/2 7/15 9/27 (33%)
0/2 3/6 5/20 (25%)
1/4 1/1 5/10 (50%)
1/2 2/3 6/11 (55%)
0/1 0/1 2/8 (25%)
1/8 0/7 1/4 4/5 7/21 (33%) 12/29 (41%)
Cardiac defects have been divided into 7 major groups (ventricular septal defect/atrial septal defect, tetralogy of Fallot, coarctation of the aorta/aortic stenosis, hypoplastic left heart, transposition of the great vessels, other, multiple anomalies). For the definition of the high threshold in each study, see Table I. Three studies (Hafner et al14, Josefsson et al15, and Schwa¨erzler et al16) did not define the types of congenital cardiac defects.
Table IV. Proportion of various types of congenital heart disease with NT measurements above the selected low-threshold in each study
Study Bilardo et al11 Hyett et al8 Michailidis and Economides18 Mavrides et al19 Orvos et al20 TOTAL
Atrial septal Coarctation of defect or ventricular the aorta or aortic septal defect (n/N) Fallot (n/N) stenosis (n/N)
Hypoplastic left heart (n/N)
Transposition of the great arteries (n/N)
Other (n/N)
Multiple anomalies (n/N)
0/1 3/6 2/2
0/0 11/17 0/0
0/0 4/8 1/2
0/1 2/9 0/2
0/0 3/3 0/2
2/2 2/2 1/2
0/0 3/5 0/1
0/2 7/15 12/27 (44%)
0/2 3/6 5/20 (25%)
1/4 1/1 5/10 (50%)
2/2 2/3 9/11 (82%)
0/1 0/1 3/8 (38%)
1/8 0/7 1/4 4/5 7/21 (33%) 15/29 (52%)
Cardiac defects have been divided into 7 major groups (ventricular septal defect/atrial septal defect, tetralogy of Fallot, coarctation of the aorta/aortic stenosis, hypoplastic left heart, transposition of the great vessels, other, multiple anomalies). For the definition of the low threshold in each study, see Table I. Three studies (Hafner et al14, Josefsson et al15, and Schwa¨erzler et al16) did not define the types of congenital cardiac defects.
The studies that were included in this meta-analysis were performed in centers that had adequate experience in NTevaluation. Most evidence comes from studies in the United Kingdom and all evidence is derived from Europe, whereas first-trimester ultrasound has not yet been adopted in the United States. Training is important for obtaining reproducible results. For centers that lack pertinent experience, the benefits of first-trimester screening for cardiac defects may be more questionable, and the resource expectations and cost-benefit may be prohibitive. The sensitivity of NT screening for major CHD is apparently at least comparable and probably better than that of routine second-trimester 4CV examination.21 The two techniques may be complementary. NT screening does not appear to select strongly any specific types of cardiac defects, whereas tetralogy of Fallot, transposition of the great vessels, coarctation of the aorta, and some other lesions rarely are detected with 4CV examination.22 Although we observed modest differences for the detection rates of various types of CHD by using NT screening, these differences were not significant and were least appreciable when the high thresholds were used.
We found that the sensitivity for major cardiac defects increases from 31% to 37% by adopting the 95th rather than the 99th percentile threshold. At present there is limited availability of specialist centers for fetal echocardiography; therefore, referral to such centers may be confined to chromosomally normal fetuses with NT above the 99th percentile. Given the estimated positive predictive value, 1 case of CHD would be detected among 16 suspected cases, if the high threshold (99th percentile) is used. Assuming that three fourths of these defects would have been missed at 4CV examination, approximately 21 detailed cardiac ultrasound examinations would need to be performed for a net additional diagnosis of a major CHD. Assuming a cost of approximately $200 per detailed cardiac scan,23 one net additional diagnosis of a major CHD would cost approximately $4200. From an interventional perspective, an acyanotic lesion that requires infant surgery may cost approximately $49,730, and a cyanotic lesion that requires operation may cost up to $102,084.24 Of course, not all couples will elect to terminate pregnancy because of an antenatal CHD diagnosis, but even if they choose to continue with pregnancy they may have more time to prepare and decide on their options.
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The mean gestational age at diagnosis of CHD has been reported to be 26.9 weeks for the total population and 29.1 weeks for the cases that are referred for detailed fetal echocardiography because of fetal abnormalities that are detected at routine ultrasound screening.5 NT screening may allow for the detection of suspicious cases at an earlier gestational age. Late first- or early second-trimester echocardiography in specialist centers may obtain diagnostic images in up to 98% of cases, with a sensitivity of approximately 75% to 80%.25 Given that many parents will choose the termination of pregnancy when CHDs are detected,25 an early diagnosis may reduce maternal morbidity significantly. NT screening for major cardiac defects appears to be superior to the traditional indications for specialist echocardiography, including family history of cardiac defects, maternal diabetes mellitus, or the injection of teratogens. Given the well-documented discriminating ability of first-trimester NT measurements for chromosomal abnormalities,7 the identification of a number of CHD cases may provide an incremental benefit. Therefore, for centers that perform routine NT measurements, detailed cardiac scans seem to be indicated in fetuses with increased NT and a normal karyotype. We thank Drs John Simpson and Janos Szabo for providing clarification and additional data on their studies and for reviewing the final draft. REFERENCES 1. Hoffman JI. Congenital heart disease: incidence and inheritance. Pediatr Clin North Am 1990;37:25-43. 2. Yang Q , Khoury M, Mannino D. Trends and patterns of mortality associated with birth defects and genetic diseases in the United States, 1979-1992: an analysis of multiple-cause morbidity data. Available from: http:/www.cdc.gov/genomics/info/reports/files/ print/trends.pdf (Update 03-07-2002). 3. Buskens E, Grobbee DE, Frohn-Mulder IM, Stewart PA, Juttmann RE, Wladimiroff JW, et al. Efficacy of routine fetal ultrasound screening for congenital heart disease in normal pregnancy. Circulation 1996;94:67-72. 4. Achiron R, Glaser J, Gelernter I, Hegesh J, Yagel S. Extended fetal echocardiographic examination for detecting cardiac malformations in low risk pregnancies. BMJ 1992;304:671-4. 5. Stu¨mpflen I, Stu¨mpflen A, Wimmer M, Bernaschek G. Effect of detailed fetal echocardiography as part of routine prenatal ultrasonographic screening on detection of congenital heart disease. Lancet 1996;348:854-7. 6. Allan LD. Echocardiographic detection of congenital heart disease in the fetus: present and future. Br Heart J 1995;74:103-6. 7. Spencer K, Souter V, Tul N, Snijders R, Nicolaides KH. A screening program for trisomy 21 at 10-14 weeks using fetal nuchal translucency, maternal serum free beta-human chorionic gonadotropin and pregnancy-associated plasma protein-A. Ultrasound Obstet Gynecol 1999;13:231-7.
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8. Hyett J, Perdu M, Sharland G, Snijders R, Nicolaides KH. Using fetal nuchal translucency to screen for major congenital cardiac defects at 10-14 weeks of gestation: population based cohort study. BMJ 1999;318:81-5. 9. Pandya PP, Snijders RJM, Johnson SP, Brizot ML, Nikolaides KH. Screening for fetal trisomies by maternal age and fetal nuchal translucency thickness at 10 to 14 weeks of gestation. BJOG 1995;102:957-62. 10. Moses LE, Shapiro D, Littenberg B. Combining independent studies of a diagnostic test into a summary ROC curve: data-analytic approaches and some additional considerations. Stat Med 1993; 12:1293-316. 11. Bilardo CM, Pajkrt E, de Graaf I, Mol BW, Bleker OP. Outcome of fetuses with enlarged nuchal translucency and normal karyotype. Ultrasound Obstet Gynecol 1998;11:401-6. 12. Brady AF, Pandya PP, Yuksel B, Greenough A, Patton MA, Nicolaides KH. Outcome of chromosomally normal livebirths with increased fetal nuchal translucency at 10-14 weeks’ gestation. J Med Genet 1998;35:222-4. 13. Pajkrt E, van Lith JM, Mol BW, Bleker OP, Bilardo CM. Screening for Down’s syndrome by fetal nuchal translucency measurement in a general obstetric population. Ultrasound Obstet Gynecol 1998; 12:163-9. 14. 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. 15. Josefsson A, Molander E, Selbing A. Nuchal translucency as a screening test for chromosomal abnormalities in a routine first trimester ultrasound examination. Acta Obstet Gynecol Scand 1998;77:497-9. 16. Schwa¨rzler P, Carvalho JS, Senat M-V, 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. 17. Simpson JM, Sharland GK. Nuchal translucency and congenital heart defects: Heart failure or not? Ultrasound Obstet Gynecol 2000;16: 30-6. 18. Michailidis GD, Economides DL. Nuchal translucency measurement and pregnancy outcome in karyotypically normal fetuses. Ultrasound Obstet Gynecol 2001;17:102-5. 19. Mavrides E, Cobian-Sanchez F, Tekay A, Moscoso G, Campbell S, Thilaganathan B, et al. Limitations using first-trimester nuchal translucency in routine screening for major congenital heart defects. Ultrasound Obstet Gynecol 2001;17:106-10. 20. Orvos H, Wayda K, Kozinsky Z, Katona M, Pa´l A, Szabo´ J. Increased nuchal translucency and congenital heart defects in euploid fetuses: the Szeged experience. Eur J Obstet Gynecol Reprod Biol 2002;101: 124-8. 21. Tegnander E, Eik-Ness SH, Johansen OJ, Linker DT. Prenatal detection of heart defects at the routine fetal examination at 18 weeks in a non-selected population. Ultrasound Obstet Gynecol 1995;5:372-80. 22. Benacerraf BR, Pober BR, Sanders SP. Accuracy of fetal echocardiography. Radiology 1987;165:847-9. 23. Roberts T, Henderson J, Mugford M, Bricker L, Neilson J, Garcia J. Antenatal ultrasound screening for fetal abnormalities: a systematic review of studies of cost and cost effectiveness. BJOG 2002;109:44-56. 24. Garson A Jr, Allen HD, Gersony WM, Gillette PC, Hohn AR, Pinsky WW, et al. The cost of congenital heart disease in children and adults: a model for assessment of price and practice variation. Arch Pediatr Adolesc Med 1994;148:1039-45. 25. Simpson JM, Jones A, Callaghan N, Sharland GK. Accuracy and limitations of transabdominal fetal echocardiography at 12-15 weeks of gestation in a population at high risk for congenital heart disease. BJOG 2000;107:1492-7.
Key words: Nuchal translucency, cardiac defect, meta-analysis
Abnormalities of the heart and the great vessels, found in 2 to 8 of every 1000 pregnancies, are the most common congenital defects and they are responsible for approximately 10% of neonatal deaths and 45% of infant deaths in the form of birth defects.1,2 Routine second-trimester ultrasound scans with a four-chamber view (4CV) have unpredictable performance for detecting congenital heart defects (CHDs),3-5 although detailed cardiac scans that are performed at specialist centers can detect most of these lesions.6 At present, referral to such specialist centers is based on maternal history of diabetes mellitus or exposure to teratogens, a family history of CHD, obvious abnormalities on ultrasound scan with a 4CV, or noncardiac defects that are known to be associated with CHD, such as diaphragmatic hernia or exomphalos. However, only 10% of the children who are born with CHD have such an identifiable risk factor.6 A promising, simple screening test for CHD is the measurement of fetal nuchal translucency (NT) at 11 to From the Department of Obstetrics and Gynaecology,a and the Clinical Trials and Evidence-Based Medicine Unit, Department of Hygiene and Epidemiology,b University of Ioannina School of Medicine, and the Division of Clinical Care Research, Tufts–New England Medical Center.c Received for publication December 4, 2002; revised April 15, 2003; accepted May 16, 2003. Reprint requests: John P.A. Ioannidis, MD, Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina 45110, Greece. E-mail: [email protected] Ó 2003, Mosby, Inc. All rights reserved. 0002-9378/2003 $30.00 + 0 doi:10.1067/S0002-9378(03)00645-8
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14 weeks of gestation. Fetal NT, in combination with maternal age and maternal serum markers, can detect approximately 90% of fetuses with trisomy 21 and other major chromosomal defects.7 In addition, several studies have shown that there is a strong association between increased NT and major cardiac defects, which suggests that this test could be used concomitantly for both chromosomal and cardiac screening. The largest study has shown a sensitivity of 56% for the detection of the severe cardiac defects among chromosomally normal fetuses.8 Other studies, however, have failed to reproduce these results, and there remains a considerable uncertainty about the exact diagnostic performance of NT for CHD. Even studies with several thousand pregnancies have relatively few CHD cases, and their results may be inconclusive when seen in isolation. It is unknown whether differences between studies may have been due to chance or may reflect genuine diversity or bias. To address these issues and to establish whether there is a role for NT measurements in screening for CHD, we performed a comprehensive meta-analysis of the available evidence.
Methods Search strategy and eligibility criteria. Studies were retrieved from MEDLINE and EMBASE searches (1985 to June 2002) with the keywords (fetal) nuchal translucency, cardiac defect, and cardiac anomalies. References of retrieved articles were also screened. All studies were compared
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carefully to assure that we avoided using duplicate reports of the same subjects. We also communicated with primary investigators and field experts to obtain additional data that were not reported clearly in published reports and to clarify study design issues. Studies were eligible if they described the presence or not of clinically significant cardiac defects in chromosomally normal fetuses that were split according to normal versus increased NT measurements in the first trimester. We accepted the definition of cardiac defects as provided by each study but generally excluded insignificant and transient cardiac defects that resolved spontaneously on subsequent examinations. Cardiac defects could have been diagnosed by fetal echocardiography, postmortem examination (in cases of fetal death), or postnatal clinical examination. In the case of data duplication or overlap, only the largest or most recent study with available data was included. Some variability across studies in the definition of significant cardiac defects and in the follow-up period of ascertainment may be unavoidable. The effect of such variability on the observed prevalence of cardiac defects is probably small compared with the effect of the background risk of the study population. Data extraction. Information was extracted on study population characteristics, age of pregnancy at which sonography was performed, inclusion and exclusion criteria, study design, outcome assessment and potential selection and verification bias, and 2 3 2 tables that classified the presence or not of cardiac defects according to different NT thresholds. Two investigators performed independent data extraction. Discrepancies were evaluated jointly with a third investigator, and consensus was reached for all data. Evaluation of diagnostic performance. The main parameters of diagnostic performance included sensitivity and specificity of increased NT for cardiac defects. Increased NT may be defined with different thresholds. Therefore, we agreed to examine two separate analyses. The first analysis (low-threshold analysis) included thresholds that corresponded to the 95th percentile (2.2-2.8 mm), depending on gestational age.9 If such data were not available in a study, we accepted a threshold of 2.5 mm, or, if this was also unavailable, 3 mm. The second analysis (high-threshold analysis) included thresholds that corresponded to the 99th percentile or, alternatively, to 3.5 mm. The two thresholds are practically equivalent, regardless of gestational age.9 If such data were not available in a study, we accepted data on the threshold closest to 3.5 mm, within the range of 3 to 5 mm. Meta-analysis. Analyses were performed separately for the high-threshold and low-threshold data. We used two methods for assessing the overall diagnostic performance of increased NT: independently combined sensitivity and specificity values and summary receiver-operating characteristic (SROC) curve analysis.
Heterogeneity of sensitivity and specificity estimates across studies was evaluated with the v2 test or Fisher exact test, as appropriate. We used both fixed and random effects models to estimate a weighted sensitivity and specificity across studies. The fixed effects model weighs each study by the inverse of its variance. Random effects incorporate both within-study and between-study variation. Random effects tend to provide wider confidence intervals and are generally preferable. The derived weighted estimates were used to estimate the positive likelihood ratio (LR+, Sensitivity/[1 Specificity]) and the negative likelihood ratio (LR, [1 Sensitivity]/Specificity). LR values are always larger than 0. A diagnostic test has no discriminating performance when the LR values are 1. The discriminating performance is better, the higher the LR+ and the smaller the LR. Independent weighted estimation of sensitivity and specificity may sometimes underestimate both, because these measures are interdependent. The SROC method accounts for this interdependence by fitting a curve that best describes the tradeoff between sensitivity and specificity across studies.10 The regression is D = a + bS, where D is the difference of the logits of the true positive rate (sensitivity) and false-positive rate (1 specificity) and S is the sum of these logits. Both weighted and unweighted SROC methods were used. Independent weighted estimates and SROC results were compared for consistency. We also estimated separately the sensitivity for different types of CHD and evaluated by the Fisher exact test whether the observed differences across CHD types were overall statistically significant. Positive predictive value. The positive predictive value of increased NT is the probability that a fetus has a cardiac defect when NT is increased (ie, P[Cardiac defect/ Increased NT]). This probability depends on the overall background prevalence P (previous probability) of cardiac defects in the study population (ie, P[Cardiac defect/Increased NT] = [P(LR+)/(1 P)]/ [1 + (P[LR+]/[1 P])]). Prevalence and LR+ values were derived from the meta-analysis. Analyses were conducted in SPSS (SPSS, Inc, Chicago, Ill), Meta-test ( Joseph Lau, Boston, Mass), and StatXact (Cytel, Inc, Boston, Mass). Results Eligible studies. The literature search identified 48 items. Sixteen were excluded on closer examination of the abstract. Of the items that were retrieved in full-text, 8 items actually did not provide the NT data, and 13 items included only cases with increased NT. Eleven reports were considered potentially eligible for the meta-analysis.8,11-20 One report was excluded13 because its study population had been described in more detail elsewhere.11 Another report was excluded12 because it was a subset of another larger study.8 Finally, we excluded one
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Table I. Descriptive characteristics of the eligible studies No. excluded Study
Gestational age (wk)
Study design
No. included
Chromosomal abnormalities
Other reasons*
Bilardo et al11 Hafner et al14 Josefsson et al15 Hyett et al8 Schwa¨rzler et al16 Michailidis and Economides18 Mavrides et al19 Orvos et al20
10-14 10-13 CRL, 31-84 mm 10-14 10-14 12-13 10-14 10-13
Prospective Prospective Prospective Retrospective Prospective Retrospective Prospective Retrospective
1,590 4,214 1,460 29,154 4,474 6,606 7,339 3,655
50 19 0 323 23 44 NDy 15
223 138 ND 1685 26 850 ND 3002
ND, Not defined. *Includes losses to follow-up and cases of fetal demise or termination of pregnancy without ascertainment of cardiac status. yAlthough the number is not stated, all chromosomal abnormalities have been excluded.
Table II. Included studies: Thresholds and results Study
NT threshold
Bilardo et al11 $3 mm Hafner et al14 $2.5 mm Josefsson et al15 $2.5 mm $3.5 mm >95th Hyett et al8 percentile >3.5 mm $2.5 mm Schwa¨rzler et al16 Michailidis >95th and percentile Economides18 >99th percentile Mavrides et al19 $2.5 mm $3.5 mm $3 mm Orvos et al20
True False False True positive negative positive negative 2 4 5 0 28
2 10 8 13 22
45 59 129 6 1794
1541 4141 1318 1441 27310
20 1
30 8
295 121
28809 4344
4
7
231
6364
3
8
70
6525
4 3 18
22 23 17
254 57 83
7059 7256 3537
study17 that described referred fetuses with suspicion for cardiac disease (based on either increased NT or other findings), but with no information available on the total number of fetuses who had NT evaluations (the population basis for the referred cases [Dr John Simpson, personal communication, June 2002]). Therefore, eight independent studies were considered in the meta-analysis. Study characteristics. In all studies (Table I), NT was measured consistently at a gestational age of 10 to 14 weeks (corresponding to a crown-rump length of 38-84 mm) as the maximal sonolucent distance between the inner border of the fetal skin and the outer border of the cervical spine in a mid sagittal section of the fetus. The eligible group excludes cases of chromosomal abnormalities in all studies; chromosomal abnormalities were detected in 0% to 2.6% of each study population. There were some differences across studies concerning the diagnostic documentation for CHD. Prenatal sonographic evaluation and/or postnatal clinical assessment had been performed routinely in all studies, but the percentage of non evaluated cases varied across studies.
Exclusions for reasons other than the presence of chromosomal abnormalities accounted for 0.6% to 13.6% of the original study population who had NT evaluations in five studies8,11,14,16,18 and were likely to be also very limited in another prospective study,15 although no exact numbers were provided. Orvos et al20 examined only the cases that were followed until delivery or fetal death specifically at the study center; thus, 45% of cases who had NT measurements were not included in the data (Dr Janos Szabo, personal communication, June 2002). Finally, in another study, no information was provided on these exclusions (Table I).19 All eight studies provided data on low thresholds, and six studies provided data on high thresholds (Table II).8,11,15,18-20 In total, the eight studies included 58,492 chromosomally normal fetuses, of which 162 fetuses had a diagnosis of cardiac defect. Data synthesis. The prevalence of CHD differed significantly among the included studies (P < .01). The prevalence was 0.2% to 0.4% in six studies and 0.9% to 1.0% in two studies. Across all eight eligible studies, cardiac defects were seen in 162 of 58,492 examined cases (0.28%). When limited to the six studies that provided data for the high-threshold analysis, the prevalence was similarly 139 of 49,804 cases (0.28%). There was significant between-study heterogeneity across studies in the specificity and sensitivity estimates; therefore, random effects are preferable over fixed-effects estimates. By random effects calculations, the independently weighted sensitivity and specificity were 37% (95% CI, 25%-51%) and 96.6% (95% CI, 95.1%-97.6%) for the low-threshold analysis and 31% (95% CI, 18%-49%) and 98.7% (95% CI, 98.1%-99.2%) for the high-threshold analysis. SROC analyses suggested similar diagnostic performance (Figure, A and B), and all the studies operated diagnostically in close proximity to the drawn SROC curves. Weighted and unweighted SROC curves were practically coinciding (Figure). Excluding the largest study,8 the sensitivity estimates were 33% (95% CI, 22%47%) and 27% (95% CI, 11%-53%) by random effects for
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the low- and high-threshold analysis, respectively, and the SROC curve was not shifted. The sensitivity of NT measurements varied somehow across different CHD types (Tables III and IV), and variability seemed more prominent in the low-threshold analyses. Nevertheless, even for lesions for which the 4CV has very poor screening performance (eg, tetralogy of Fallot, transposition of great vessels, coarctation of the aorta, and aortic stenosis), sensitivity varied between 25% and 50% with the high threshold (Table III). Movement to the low threshold did not seem to improve the detection rate for these difficult-to-diagnose CHD types (Table IV). The differences between various types of lesions could have been due to chance, given the small numbers of cases in each type of CHD, but modest differences cannot be excluded, especially for the lowthreshold analyses (exact P = .64 for high-threshold, P = .08 for low-threshold). The random effects estimates corresponded to an LR+ of 11 and an LR of 0.65 for the low-threshold analysis and an LR+ of 24 and an LR of 0.70 for the highthreshold analysis. The LR+ values suggest that the positive predictive value in a population with 0.28% prevalence of CHD is approximately 3% and 6%, respectively, for low- and high-threshold calculations.
Comment The findings of this meta-analysis demonstrate a significant association between increased NT and CHD. Despite the strong statistical significance, the clinical efficiency for the detection of cardiac lesions is modest. Approximately 30% of fetuses with major cardiac defects may be identified by specialist echocardiography in chromosomally normal fetuses with NT above the 99th percentile. Most fetuses with increased NT have a normal heart: 1 in 33 fetuses who are referred for detailed cardiac echocardiography because of NT above the 95th percentile would have a major cardiac defect detected. If the 99th percentile were used for detailed cardiac screening, 1 in 16 referred cases would have a major cardiac defect detected. We recorded no obvious strong verification bias in the analyzed studies, and the numbers of losses to follow-up and of dead fetuses with insufficient documentation of cardiac status were not large enough to change these conclusions. Nevertheless, some verification bias may be unavoidable, because increased NT may have led to a more intensive investigation for CHD. Such bias may be expected to be stronger for NT measurements above the high threshold, and this may offer an explanation for the apparently small increase in sensitivity when moving from the 99th to the 95th percentiles. However, verification bias might have been more prominent for cases with fewer severe cardiac defects that would not have come to medical attention, even after birth. Variable postnatal follow-up
Figure. SROC analyses for the ‘‘low-threshold’’ (A) and ‘‘highthreshold’’ (B) analyses. Each study is shown by a circle that denotes its true-positive rate (sensitivity) and false-positive rate (1 Specificity). Also shown are the SROC curves for weighted (thick line) and unweighted (thin line) analyses. The crosses denote the independently weighted sensitivity and specificity estimates across all studies by random effects estimation; the shaded boxes show the corresponding 95% CIs.
in these studies may also cause variable verification bias. However, cases that were diagnosed in late postnatal follow-up contribute less to death and morbidity than the major CHD that were considered in this meta-analysis.
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Table III. Proportion of various types of congenital heart disease with NT measurements above the selected high-threshold in each study
Study Bilardo et al11 Hyett et al8 Michailidis and Economides18 Mavrides et al19 Orvos et al20 TOTAL
Atrial septal defect or ventricular septal defect (n/N)
Fallot (n/N)
Coarctation of the aorta or aortic stenosis (n/N)
Hypoplastic left heart (n/N)
Transposition of the great arteries (n/N)
Other (n/N)
Multiple anomalies (n/N)
0/0 1/8 1/2
0/1 2/9 0/2
0/0 3/3 0/2
2/2 1/2 0/2
0/0 2/5 0/1
0/1 3/6 2/2
0/0 8/17 0/0
0/2 7/15 9/27 (33%)
0/2 3/6 5/20 (25%)
1/4 1/1 5/10 (50%)
1/2 2/3 6/11 (55%)
0/1 0/1 2/8 (25%)
1/8 0/7 1/4 4/5 7/21 (33%) 12/29 (41%)
Cardiac defects have been divided into 7 major groups (ventricular septal defect/atrial septal defect, tetralogy of Fallot, coarctation of the aorta/aortic stenosis, hypoplastic left heart, transposition of the great vessels, other, multiple anomalies). For the definition of the high threshold in each study, see Table I. Three studies (Hafner et al14, Josefsson et al15, and Schwa¨erzler et al16) did not define the types of congenital cardiac defects.
Table IV. Proportion of various types of congenital heart disease with NT measurements above the selected low-threshold in each study
Study Bilardo et al11 Hyett et al8 Michailidis and Economides18 Mavrides et al19 Orvos et al20 TOTAL
Atrial septal Coarctation of defect or ventricular the aorta or aortic septal defect (n/N) Fallot (n/N) stenosis (n/N)
Hypoplastic left heart (n/N)
Transposition of the great arteries (n/N)
Other (n/N)
Multiple anomalies (n/N)
0/1 3/6 2/2
0/0 11/17 0/0
0/0 4/8 1/2
0/1 2/9 0/2
0/0 3/3 0/2
2/2 2/2 1/2
0/0 3/5 0/1
0/2 7/15 12/27 (44%)
0/2 3/6 5/20 (25%)
1/4 1/1 5/10 (50%)
2/2 2/3 9/11 (82%)
0/1 0/1 3/8 (38%)
1/8 0/7 1/4 4/5 7/21 (33%) 15/29 (52%)
Cardiac defects have been divided into 7 major groups (ventricular septal defect/atrial septal defect, tetralogy of Fallot, coarctation of the aorta/aortic stenosis, hypoplastic left heart, transposition of the great vessels, other, multiple anomalies). For the definition of the low threshold in each study, see Table I. Three studies (Hafner et al14, Josefsson et al15, and Schwa¨erzler et al16) did not define the types of congenital cardiac defects.
The studies that were included in this meta-analysis were performed in centers that had adequate experience in NTevaluation. Most evidence comes from studies in the United Kingdom and all evidence is derived from Europe, whereas first-trimester ultrasound has not yet been adopted in the United States. Training is important for obtaining reproducible results. For centers that lack pertinent experience, the benefits of first-trimester screening for cardiac defects may be more questionable, and the resource expectations and cost-benefit may be prohibitive. The sensitivity of NT screening for major CHD is apparently at least comparable and probably better than that of routine second-trimester 4CV examination.21 The two techniques may be complementary. NT screening does not appear to select strongly any specific types of cardiac defects, whereas tetralogy of Fallot, transposition of the great vessels, coarctation of the aorta, and some other lesions rarely are detected with 4CV examination.22 Although we observed modest differences for the detection rates of various types of CHD by using NT screening, these differences were not significant and were least appreciable when the high thresholds were used.
We found that the sensitivity for major cardiac defects increases from 31% to 37% by adopting the 95th rather than the 99th percentile threshold. At present there is limited availability of specialist centers for fetal echocardiography; therefore, referral to such centers may be confined to chromosomally normal fetuses with NT above the 99th percentile. Given the estimated positive predictive value, 1 case of CHD would be detected among 16 suspected cases, if the high threshold (99th percentile) is used. Assuming that three fourths of these defects would have been missed at 4CV examination, approximately 21 detailed cardiac ultrasound examinations would need to be performed for a net additional diagnosis of a major CHD. Assuming a cost of approximately $200 per detailed cardiac scan,23 one net additional diagnosis of a major CHD would cost approximately $4200. From an interventional perspective, an acyanotic lesion that requires infant surgery may cost approximately $49,730, and a cyanotic lesion that requires operation may cost up to $102,084.24 Of course, not all couples will elect to terminate pregnancy because of an antenatal CHD diagnosis, but even if they choose to continue with pregnancy they may have more time to prepare and decide on their options.
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The mean gestational age at diagnosis of CHD has been reported to be 26.9 weeks for the total population and 29.1 weeks for the cases that are referred for detailed fetal echocardiography because of fetal abnormalities that are detected at routine ultrasound screening.5 NT screening may allow for the detection of suspicious cases at an earlier gestational age. Late first- or early second-trimester echocardiography in specialist centers may obtain diagnostic images in up to 98% of cases, with a sensitivity of approximately 75% to 80%.25 Given that many parents will choose the termination of pregnancy when CHDs are detected,25 an early diagnosis may reduce maternal morbidity significantly. NT screening for major cardiac defects appears to be superior to the traditional indications for specialist echocardiography, including family history of cardiac defects, maternal diabetes mellitus, or the injection of teratogens. Given the well-documented discriminating ability of first-trimester NT measurements for chromosomal abnormalities,7 the identification of a number of CHD cases may provide an incremental benefit. Therefore, for centers that perform routine NT measurements, detailed cardiac scans seem to be indicated in fetuses with increased NT and a normal karyotype. We thank Drs John Simpson and Janos Szabo for providing clarification and additional data on their studies and for reviewing the final draft. REFERENCES 1. Hoffman JI. Congenital heart disease: incidence and inheritance. Pediatr Clin North Am 1990;37:25-43. 2. Yang Q , Khoury M, Mannino D. Trends and patterns of mortality associated with birth defects and genetic diseases in the United States, 1979-1992: an analysis of multiple-cause morbidity data. Available from: http:/www.cdc.gov/genomics/info/reports/files/ print/trends.pdf (Update 03-07-2002). 3. Buskens E, Grobbee DE, Frohn-Mulder IM, Stewart PA, Juttmann RE, Wladimiroff JW, et al. Efficacy of routine fetal ultrasound screening for congenital heart disease in normal pregnancy. Circulation 1996;94:67-72. 4. Achiron R, Glaser J, Gelernter I, Hegesh J, Yagel S. Extended fetal echocardiographic examination for detecting cardiac malformations in low risk pregnancies. BMJ 1992;304:671-4. 5. Stu¨mpflen I, Stu¨mpflen A, Wimmer M, Bernaschek G. Effect of detailed fetal echocardiography as part of routine prenatal ultrasonographic screening on detection of congenital heart disease. Lancet 1996;348:854-7. 6. Allan LD. Echocardiographic detection of congenital heart disease in the fetus: present and future. Br Heart J 1995;74:103-6. 7. Spencer K, Souter V, Tul N, Snijders R, Nicolaides KH. A screening program for trisomy 21 at 10-14 weeks using fetal nuchal translucency, maternal serum free beta-human chorionic gonadotropin and pregnancy-associated plasma protein-A. Ultrasound Obstet Gynecol 1999;13:231-7.
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8. Hyett J, Perdu M, Sharland G, Snijders R, Nicolaides KH. Using fetal nuchal translucency to screen for major congenital cardiac defects at 10-14 weeks of gestation: population based cohort study. BMJ 1999;318:81-5. 9. Pandya PP, Snijders RJM, Johnson SP, Brizot ML, Nikolaides KH. Screening for fetal trisomies by maternal age and fetal nuchal translucency thickness at 10 to 14 weeks of gestation. BJOG 1995;102:957-62. 10. Moses LE, Shapiro D, Littenberg B. Combining independent studies of a diagnostic test into a summary ROC curve: data-analytic approaches and some additional considerations. Stat Med 1993; 12:1293-316. 11. Bilardo CM, Pajkrt E, de Graaf I, Mol BW, Bleker OP. Outcome of fetuses with enlarged nuchal translucency and normal karyotype. Ultrasound Obstet Gynecol 1998;11:401-6. 12. Brady AF, Pandya PP, Yuksel B, Greenough A, Patton MA, Nicolaides KH. Outcome of chromosomally normal livebirths with increased fetal nuchal translucency at 10-14 weeks’ gestation. J Med Genet 1998;35:222-4. 13. Pajkrt E, van Lith JM, Mol BW, Bleker OP, Bilardo CM. Screening for Down’s syndrome by fetal nuchal translucency measurement in a general obstetric population. Ultrasound Obstet Gynecol 1998; 12:163-9. 14. 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. 15. Josefsson A, Molander E, Selbing A. Nuchal translucency as a screening test for chromosomal abnormalities in a routine first trimester ultrasound examination. Acta Obstet Gynecol Scand 1998;77:497-9. 16. Schwa¨rzler P, Carvalho JS, Senat M-V, 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. 17. Simpson JM, Sharland GK. Nuchal translucency and congenital heart defects: Heart failure or not? Ultrasound Obstet Gynecol 2000;16: 30-6. 18. Michailidis GD, Economides DL. Nuchal translucency measurement and pregnancy outcome in karyotypically normal fetuses. Ultrasound Obstet Gynecol 2001;17:102-5. 19. Mavrides E, Cobian-Sanchez F, Tekay A, Moscoso G, Campbell S, Thilaganathan B, et al. Limitations using first-trimester nuchal translucency in routine screening for major congenital heart defects. Ultrasound Obstet Gynecol 2001;17:106-10. 20. Orvos H, Wayda K, Kozinsky Z, Katona M, Pa´l A, Szabo´ J. Increased nuchal translucency and congenital heart defects in euploid fetuses: the Szeged experience. Eur J Obstet Gynecol Reprod Biol 2002;101: 124-8. 21. Tegnander E, Eik-Ness SH, Johansen OJ, Linker DT. Prenatal detection of heart defects at the routine fetal examination at 18 weeks in a non-selected population. Ultrasound Obstet Gynecol 1995;5:372-80. 22. Benacerraf BR, Pober BR, Sanders SP. Accuracy of fetal echocardiography. Radiology 1987;165:847-9. 23. Roberts T, Henderson J, Mugford M, Bricker L, Neilson J, Garcia J. Antenatal ultrasound screening for fetal abnormalities: a systematic review of studies of cost and cost effectiveness. BJOG 2002;109:44-56. 24. Garson A Jr, Allen HD, Gersony WM, Gillette PC, Hohn AR, Pinsky WW, et al. The cost of congenital heart disease in children and adults: a model for assessment of price and practice variation. Arch Pediatr Adolesc Med 1994;148:1039-45. 25. Simpson JM, Jones A, Callaghan N, Sharland GK. Accuracy and limitations of transabdominal fetal echocardiography at 12-15 weeks of gestation in a population at high risk for congenital heart disease. BJOG 2000;107:1492-7.