SEARCH

SEARCH BY CITATION

Keywords:

  • first-trimester screening;
  • free β-hCG;
  • nuchal translucency;
  • PAPP-A;
  • trisomy 21

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Objectives

To derive a model and examine the performance of first-trimester combined screening by maternal age, fetal nuchal translucency (NT) thickness and maternal serum free beta-human chorionic gonadotropin (β-hCG) and pregnancy-associated plasma protein-A (PAPP-A).

Methods

Prospective combined screening for trisomy 21 was carried out at 11 + 0 to 13 + 6 weeks in 56 771 singleton pregnancies, including 56 376 cases with a normal karyotype or delivery of a phenotypically normal baby (unaffected group) and 395 cases with trisomy 21. The blood test and ultrasound scan were carried out in the same visit. In each case the maternal age-related risk for trisomy 21 at term was calculated and adjusted according to the gestational age at the time of screening to derive the a-priori risk. The measured NT was transformed into a likelihood ratio using the mixture model of NT distributions. The measured free β-hCG and PAPP-A were converted into a multiple of the median (MoM) for gestational age, adjusted for maternal weight, ethnicity, smoking status, method of conception and parity, and a likelihood ratio was subsequently calculated. The likelihood ratios for NT and for the biochemical markers were multiplied by the a-priori risk to derive the patient-specific risk. Detection rates and false-positive rates were calculated by taking the proportions with risks above a given risk threshold after adjustment for maternal age according to the distribution of pregnancies in England and Wales in 2000–2002. These standardized rates were compared with detection and false-positive rates estimated using Monte Carlo methods to sample from the modeled Gaussian distributions.

Results

The performance of screening based on the model was in good agreement with that observed in our population. In a strategy for first-trimester combined screening where the blood test and scan are carried out in the same visit it was estimated that, for false-positive rates of 3% and 5%, the detection rates were 92% and 94%, respectively, at 11 weeks, 85% and 90% at 12 weeks, and 79% and 83% at 13 weeks. In an alternative strategy, with the blood taken at 10 weeks and the measurement of NT performed at 12 weeks, the estimated detection rates were 94% and 96% for false-positive rates of 3% and 5%, respectively.

Conclusions

The aim of the first-trimester scan is not just to screen for trisomy 21 but also to diagnose an increasing number of fetal malformations. In this respect the ability to visualize fetal anatomy is better at 12–13 weeks than at 11 weeks. Consequently, the ideal gestation for combined testing in the same visit would be 12 weeks. An alternative strategy, with the blood taken at 10 weeks and the measurement of NT performed at 12 weeks, is associated with higher detection rates of trisomy 21. However, the cost of two-stage screening would be higher and, in addition, the potential advantage in terms of detection rate may be eroded by the likely increased non-compliance with the additional step. Copyright © 2008 ISUOG. Published by John Wiley & Sons, Ltd.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Effective screening for trisomy 21 is provided by assessment of a combination of maternal age, fetal nuchal translucency (NT) thickness, and maternal serum free beta-human chorionic gonadotropin (β-hCG) and pregnancy-associated plasma protein-A (PAPP-A) at 11 to 13 + 6 weeks of gestation1, 2. Prospective studies have demonstrated that, for a false-positive rate of 5%, combined screening can identify about 90% of affected fetuses3, 4. In the assessment of patient-specific risks, the a-priori maternal age-related risk is multiplied by likelihood ratios, determined from the deviation of the measured NT, free β-hCG and PAPP-A from the respective expected median.

The traditional approaches to quantifying the deviation in the measured NT from the normal median for crown–rump length (CRL) have been either by subtraction (delta NT method) or by division (multiples of the median (MoM) method). However, we have recently proposed a new approach based on the observation that in both trisomy 21 and unaffected pregnancies fetal NT follows two distributions, one which is CRL dependent and another which is CRL independent5. In this mixture model the proportions of trisomy 21 and unaffected fetuses that follow the CRL-independent distribution are 95% and 5%, respectively. The detection rate of a screening policy based on maternal age and the mixture model of fetal NT was 80% for a 5% false-positive rate5.

In biochemical testing it is necessary to make adjustments in the measured maternal serum concentration of free β-hCG and PAPP-A to correct for certain maternal and pregnancy characteristics. Essentially, each measured level is first converted to a multiple of the expected normal median (MoM) specific to a pregnancy of the same gestational age, maternal weight, ethnicity, smoking status, method of conception and parity, as well as the machine and reagents used for the assays. In a recent study of 491 pregnancies with trisomy 21 and 96 803 unaffected pregnancies we used multiple regression analysis to define the contribution of maternal variables that influence the measured concentration of free β-hCG and PAPP-A, and the interaction between these covariates6. The traditional method of sequential adjustment for each individual parameter fails to take into account the interaction between the covariates7. The detection rate of a screening policy based on maternal age and the two biochemical markers was 65% for a 5% false-positive rate6.

In this study of more than 56 000 normal pregnancies and 395 cases with trisomy 21 we used the mixture model for fetal NT5 and the new estimates for free β-hCG and PAPP-A based on the multiple regression approach6 to examine the performance of first-trimester combined screening by maternal age, fetal NT, and maternal serum free β-hCG and PAPP-A.

Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

At the Fetal Medicine Centre, London, screening for trisomy 21 is carried out by a combination of maternal age, fetal NT thickness, and maternal serum free β-hCG and PAPP-A in a one-stop-clinic for first-trimester assessment of risk at 11 + 0 to 13 + 6 weeks of gestation3. Transabdominal ultrasound examination is performed to diagnose any major fetal defects, and for measurement of CRL and fetal NT thickness1. The Kryptor system (Brahms AG, Berlin, Germany) is used to measure PAPP-A and free β-hCG. Maternal demographic characteristics, ultrasonographic measurements and biochemical results are recorded in a computer database. Karyotype results and details of pregnancy outcomes are added to the database as soon as they become available. A search of the database was done to identify all singleton pregnancies in which first-trimester combined screening was carried out from July 1999 to July 2007.

Statistical analysis

The following steps were taken. First, the maternal age-related risk for trisomy 21 at term was calculated and adjusted according to the gestational age at the time of screening8, 9. Second, the measured NT was transformed into a likelihood ratio using the mixture model of NT distributions5. Third, the measured free β-hCG and PAPP-A were converted into a MoM for gestational age, adjusted for maternal weight, ethnicity, smoking status, method of conception and parity, and subsequently a likelihood ratio was calculated from the fitted bivariate Gaussian distributions in trisomy 21 and unaffected pregnancies. Fourth, the likelihood ratios for NT and for the biochemical markers were multiplied by the age-related risk at the time of screening in each case. Fifth, detection rates and false-positive rates were calculated by taking the proportions with risks above a given risk threshold after adjustment for maternal age, according to the distribution of pregnancies in England and Wales in 2000–200210. These standardized rates were compared with detection and false-positive rates estimated using Monte Carlo methods to sample from the modeled Gaussian distributions5, 6.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

The search of the database identified 60 172 singleton pregnancies. In 3053 (5.1%) cases the outcome or one of the covariates were not available and in 348 (0.6%) cases there was a chromosomal abnormality other than trisomy 21. Thus, our study population consisted of 56 376 pregnancies with a normal karyotype or delivery of a phenotypically normal baby (unaffected group) and 395 cases with trisomy 21. The characteristics of the study population are summarized in Table 1. According to the maternal age distribution of our population and the gestational age at the time of screening we would have expected 367 (95% prediction interval, 329–405) cases with trisomy 219.

Table 1. Characteristics of the study population of 56 771 women
ParameterMedian (range) or n (%)
Maternal characteristics
 Age (years)35.4 (14.1–52.5)
 Weight (kg)63.6 (34.0–165.0)
 Spontaneous conception54 135 (95.4)
 Smoker2566 (4.5)
Ethnicity
 Caucasian50 708 (89.3)
 Afro-Caribbean2430 (4.3)
 East Asian640 (1.1)
 South Asian2218 (3.9)
 Mixed775 (1.4)
Gestational age
 11 + 0 to 11 + 6 weeks5546 (9.8)
 12 + 0 to 12 + 6 weeks31 883 (56.2)
 13 + 0 to 13 + 6 weeks19 342 (34.1)
Crown–rump length (mm)62.9 (45.0–84.0)
Karyotype
 Normal56 376 (99.3)
 Trisomy 21395 (0.7)

The distribution of NT in trisomy 21 fetuses is shown in Figure 1. In about 5% of cases the NT followed the CRL-dependent distribution of unaffected pregnancies, whereas in 95% of cases the NT did not change with gestation and in this group the mean (SD) NT was 3.4 (1.6) mm. Contour plots for free β-hCG and PAPP-A in trisomy 21 and unaffected pregnancies are shown in Figure 2. In the unaffected pregnancies the median free β-hCG was 1.0 (range, 0.03–30.4) MoM and the median PAPP-A was 1.0 (range, 0.02–7.9) MoM. In the trisomy 21 pregnancies the median free β-hCG was 2.0 (range, 0.1–11.3) MoM and the median PAPP-A was 0.5 (range, 0.05–2.2) MoM. In the trisomy 21 pregnancies there was a significant increase in log MoM PAPP-A (P < 0.0001) and log MoM free β-hCG (P = 0.039) with gestation (Figure 3).

thumbnail image

Figure 1. Distribution of nuchal translucency thickness with respect to crown–rump length (CRL) in trisomy 21 fetuses. In this mixture model the nuchal translucency thickness in 5% of cases follows the CRL-dependent distribution (dark shaded area with median and 5th and 95th centiles) and in 95% of cases nuchal translucency does not change with gestation and the mean is 3.4 mm (light shaded bells).

Download figure to PowerPoint

thumbnail image

Figure 2. Distribution of multiples of the median (MoM) values for free beta-human chorionic gonadotropin (β-hCG) and pregnancy-associated plasma protein-A (PAPP-A) in chromosomally normal pregnancies (90% contour, unshaded) and in trisomy 21 pregnancies (90% contour, shaded). Raw data for our sample of 395 cases of trisomy 21 are plotted (⧫).

Download figure to PowerPoint

thumbnail image

Figure 3. Individual values and regression lines (——) of log multiples of the median (MoM) free beta-human chorionic gonadotropin (β-hCG) (a) and pregnancy-associated plasma protein-A (PAPP-A) (b) in trisomy 21 pregnancies with respect to gestational age. The dashed line is the regression line in normal pregnancies.

Download figure to PowerPoint

Performance of screening for trisomy 21 by maternal age alone, maternal age and serum biochemistry, maternal age and fetal NT, and combined screening is compared in Figure 4. For a 5% false-positive rate the respective detection rates were 30%, 65%, 80% and 91%. The performance of screening for different risk cut-offs varied with maternal age (Figure 5). For example, at a risk cut-off of 1 in 100, the detection rates for a 20-, 30- and 40-year-old woman were 72%, 77% and 92%, respectively, for a false-positive rate of 1.1%, 1.9% and 9.9%, respectively.

thumbnail image

Figure 4. Receiver–operating characteristics curves for the performance of screening for trisomy 21 by maternal age alone (——); maternal age, serum free beta-human chorionic gonadotropin and pregnancy-associated plasma protein-A ( - - - - ); maternal age and fetal nuchal translucency thickness ( · · · · · · ) and combined screening (equation image).

Download figure to PowerPoint

thumbnail image

Figure 5. Performance of combined first-trimester screening for trisomy 21. Modeled detection rate (a) and false-positive rate (b) for risk cut-offs of 1 in 300 (equation image), 1 in 200 ( · · · · · · ), 1 in 150 ( - - - - ) and 1 in 100 ( —— ) in relation to maternal age.

Download figure to PowerPoint

In combined screening the detection rates for fixed false-positive rates observed in our population, after adjustment for maternal age according to the distribution of pregnancies in England and Wales in 2000–2002, were compared with the values derived from the modeled Gaussian distributions (Table 2). These values indicate that the performance of screening based on the model is in good agreement with that observed in our population. This is further highlighted by the data presented in Table 3, where for each range of estimated risks according to the model there is good agreement with the number of observed cases of trisomy 21. Table 4 shows the modeled detection and false-positive rates for different risk cut-offs. The risk was 1 in 200 or higher in 89% of trisomy 21 and in 4.6% of the unaffected pregnancies. Table 5 shows the estimated detection rates of trisomy 21 with a policy of biochemical testing and ultrasound scanning carried out at two separate visits, with the first done at 10 or 11 weeks and the second at 12–13 weeks.

Table 2. Detection rates of trisomy 21 for given false-positive rates observed in our population, after adjustment for maternal age according to the distribution of pregnancies in England and Wales in 2000–2002, compared with values derived from the modeled Gaussian distributions
False-positive rate (%)Detection rate (%)
Overall (n = 395)11 weeks (n = 28)12 weeks (n = 223)13 + weeks (n = 144)
ObservedModeledObservedModeledObservedModeledObservedModeled
17875788384767769
28481818888838475
38984909291858679
49086959391888981
59189969492909083
Table 3. Accuracy of estimated risk of trisomy 21 by a combination of maternal age, fetal nuchal translucency thickness, and maternal serum free beta-human chorionic gonadotropin and pregnancy-associated plasma protein-A
Estimated risk of trisomy 21Trisomy 21 (n (%))Unaffected (n (%))Observed risk
RangeMedian
≥ 1 in 101 in 5273 (69.1)340 (0.6)1 in 2
1 in 11 to 1 in 501 in 2860 (15.2)909 (1.6)1 in 16
1 in 51 to 1 in 1001 in 7416 (4.1)947 (1.7)1 in 60
1 in 101 to 1 in 2501 in 17315 (3.8)2305 (4.1)1 in 155
1 in 251 to 1 in 10001 in 57919 (4.8)7362 (13.1)1 in 388
1 in 1001 to 1 in 50001 in 244310 (2.5)16 685 (29.6)1 in 1 670
< 1 in 50001 in 16 1442 (0.5)27 828 (49.4)1 in 13 915
Table 4. Modeled detection rates (DRs) and false-positive rates (FPRs) for given risk cut-offs for trisomy 21
Risk cut-offTotal11 weeks12 weeks13 weeks
DR (%)FPR (%)DR (%)FPR (%)DR (%)FPR (%)DR (%)FPR (%)
1 in 20710.6780.6710.6620.5
1 in 50791.4861.4791.4711.3
1 in 100842.6902.5852.5772.5
1 in 150873.6923.5873.5813.6
1 in 200894.6934.3894.5834.7
1 in 300916.3955.8916.1866.7
1 in 10009515.99813.39615.29317.9
Table 5. Estimated detection rates of trisomy 21 from different policies on screening according to the timing of biochemical testing and ultrasound scanning
False-positive rate (%)Detection rate (%)
Scan and blood at same visitScan 12 weeksScan 13 weeks
11 weeks12 weeks13 weeksBlood 10 weeksBlood 11 weeksBlood 10 weeksBlood 11 weeks
183766988818578
288837592879083
392857994899286
493888195919488
594908396929590
1097948998969794

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

This study shows that screening by maternal age, fetal NT, free β-hCG and PAPP-A identifies about 90% of all pregnancies with trisomy 21 for a false-positive rate of 5%, and that screening at 11 weeks of gestation performs substantially better than at 13 weeks. It also demonstrates that there is good agreement between the estimated risks derived from the model and the results in our study population.

In the calculation of patient-specific risk for trisomy 21 the maternal age-related a-priori risk is multiplied by the likelihood ratios for the fetal NT and maternal serum biochemical markers. Consequently, for the same measurements of NT, free β-hCG and PAPP-A the final risk will vary with maternal age, and for the same risk cut-off both the detection and false-positive rates increase with maternal age (Figure 5). This information, which is often requested by patients, may be useful in counseling. Furthermore, it is essential in comparing overall detection and false-positive rates between centers or against a national standard because the overall performance depends on the maternal age distribution of the screened population.

The National Screening Committee in the UK recommended that a screening test for trisomy 21 should provide an overall detection rate of at least 75% for a false-positive rate of 3% or less11. In our study both the modeled and observed detection rate of 75% was achieved at a false-positive rate of 1%. At a false-positive rate of 3% the observed and modeled detection rates were 89% and 84%, respectively. These detection rates are higher than the respective 53% and 60% achieved by the triple and quadruple second-trimester biochemical tests12. Furthermore, the performance of our combined model is substantially superior to that in two previous multicenter studies in the UK and USA13, 14. The Serum, Urine and Ultrasound Screening Study (SURUSS) recruited 47 053 pregnancies, including 101 with trisomy 21, but NT was measured in only 39 983 cases, including 85 with trisomy 21; free β-hCG and PAPP-A were measured retrospectively in stored samples from 98 trisomy 21 pregnancies and 1090 matched unaffected controls13. The modeled detection rates from combined screening were 68%, 79% and 84% for respective false-positive rates of 1%, 3% and 5%. Similarly, in the First- and Second-Trimester Evaluation of Risk (FASTER) study, 38 167 pregnancies were recruited, including 117 with trisomy 21; free β-hCG and PAPP-A were measured retrospectively in stored samples from 79 trisomy 21 pregnancies and 395 matched unaffected controls14. The modeled detection rates at 12 weeks were 72% and 85% for respective false-positive rates of 1% and 5%.

The performance of combined screening for trisomy 21 decreased with gestation and, for a 3% false-positive rate, the estimated detection rate was 92%, 85% and 79% at 11, 12 and 13 weeks, respectively. This is a consequence of both fetal NT and serum PAPP-A. In the mixture model of NT the overlap between the CRL-dependent and CRL-independent distribution increases with gestation, and therefore the separation between trisomy 21 and unaffected pregnancies decreases. Similarly, the separation in maternal serum PAPP-A between trisomy 21 and unaffected pregnancies decreases with gestation. Although there is an increase in the separation for free β-hCG with gestation this is considerably less than the decrease observed for PAPP-A. The implications of these findings are that, in terms of the performance of screening for trisomy 21 in a set-up in which biochemical testing and the ultrasound scan are carried out in the same visit, the best gestational age is 11 weeks. However, the aim of the first-trimester scan is not just to screen for trisomy 21 but also to diagnose an increasing number of fetal malformations, and in this respect the ability to visualize fetal anatomy is better at 12–13 weeks than at 11 weeks15. Consequently, the ideal gestation for combined testing in the same visit would be 12 weeks when, for false-positive rates of 3% and 5%, the estimated detection rates of trisomy 21 are 85% and 90%, respectively.

An alternative strategy for first-trimester combined screening is for biochemical testing and ultrasound scanning to be carried out in two separate visits, with the first done at 10–11 weeks and the second at 12–13 weeks. For false-positive rates of 3% and 5%, the estimated detection rates of combined testing with the blood taken at 10 weeks and the measurement of NT performed at 12 weeks are 94% and 96%, respectively. The cost and patient acceptability of the two alternative policies of first-trimester testing will depend on the existing infrastructure of antenatal care. The potential advantage of two-stage screening in terms of detection rate may be eroded by the likely increased non-compliance with the additional step. Another element to be considered in terms of alternative policies of early screening is the contribution of additional sonographic markers, such as absent nasal bone, wide frontomaxillary facial angle, reversed end-diastolic flow in the ductus venosus and tricuspid regurgitation, which have already been incorporated into routine practice in some specialist centers3, 16–19.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

This study was supported by a grant from The Fetal Medicine Foundation (charity number 1037116).

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References
  • 1
    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: 343346.
  • 2
    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: 231237.
  • 3
    Nicolaides KH, Spencer K, Avgidou K, Faiola S, Falcon O. Multicenter study of first-trimester screening for trisomy 21 in 75 821 pregnancies: results and estimation of the potential impact of individual risk-orientated two-stage first-trimester screening. Ultrasound Obstet Gynecol 2005; 25: 221226.
  • 4
    Nicolaides KH. Nuchal translucency and other first-trimester sonographic markers of chromosomal abnormalities. Am J Obstet Gynecol 2004; 191: 4567.
  • 5
    Wright D, Kagan KO, Molina FS, Gazzoni A, Nicolaides KH. A mixture model of nuchal translucency thickness in screening for chromosomal defects. Ultrasound Obstet Gynecol 2008; 31: 376383.
  • 6
    Kagan KO, Wright D, Spencer K, Molina FS, Nicolaides KH. First-trimester screening for trisomy 21 by free beta-human chorionic gonadotropin and pregnancy-associated plasma protein-A: impact of maternal and pregnancy characteristics. Ultrasound Obstet Gynecol 2008; 31: 493502.
  • 7
    Draper N, Smith R. Applied Regression Analysis (3rd edn). Wiley: New York, NY, 1998.
  • 8
    Cuckle HS, Wald NJ, Thompson SG. Estimating a woman's risk of having a pregnancy associated with Down's syndrome using her age and serum alpha-fetoprotein level. Br J Obstet Gynaecol 1987; 94: 387402.
  • 9
    Snijders RJ, Sundberg K, Holzgreve W, Henry G, Nicolaides KH. Maternal age- and gestation-specific risk for trisomy 21. Ultrasound Obstet Gynecol 1999; 13: 167170.
  • 10
    Office for National Statistics. Birth Statistics. Review of the Registrar General on births and patterns of family building in England and Wales. Series FM1, number 29–31. Stationery Office: London, 2000–2002.
  • 11
    National Screening Committee. National Screening Committee Policy—Down's Syndrome Screening (compiled July 2006). http://www.library.nhs.uk/screening/ViewResource.aspx?resID = 35689 [Accessed 23 December 2007].
  • 12
    Cuckle H, Benn P, Wright D. Down syndrome screening in the first and/or second trimester: model predicted performance using meta-analysis parameters. Semin Perinatol 2005; 29: 252257.
  • 13
    Wald NJ, Rodeck C, Hackshaw AK, Walters J, Chitty L, Mackinson AM; SURUSS Research Group. First and second trimester antenatal screening for Down's syndrome: the results of the Serum, Urine and Ultrasound Screening Study (SURUSS). Health Technol Assess 2003; 7: 177.
  • 14
    Malone FD, Canick JA, Ball RH, Nyberg DA, Comstock CH, Bukowski R, Berkowitz RL, Gross SJ, Dugoff L, Craigo SD, Timor-Tritsch IE, Carr SR, Wolfe HM, Dukes K, Bianchi DW, Rudnicka AR, Hackshaw AK, Lambert-Messerlian G, Wald NJ, D'Alton ME; First- and Second-Trimester Evaluation of Risk (FASTER) Research Consortium. First-trimester or second-trimester screening, or both, for Down's syndrome. N Engl J Med 2005; 353: 20012011.
  • 15
    Souka AP, Pilalis A, Kavalakis Y, Kosmas Y, Antsaklis P, Antsaklis A. Assessment of fetal anatomy at the 11–14-week ultrasound examination. Ultrasound Obstet Gynecol 2004; 24: 730734.
  • 16
    Cicero S, Curcio P, Papageorghiou A, Sonek J, Nicolaides K. Absence of nasal bone in fetuses with trisomy 21 at 11–14 weeks of gestation: an observational study. Lancet 2001; 358: 16651667.
  • 17
    Sonek J, Borenstein M, Dagklis T, Persico N, Nicolaides KH. Frontomaxillary facial angle in fetuses with trisomy 21 at 11–13(6) weeks. Am J Obstet Gynecol 2007; 196: 271.e1271.e4.
  • 18
    Matias A, Gomes C, Flack N, Montenegro N, Nicolaides KH. Screening for chromosomal abnormalities at 11–14 weeks: the role of ductus venosus blood flow. Ultrasound Obstet Gynecol 1998; 2: 380384.
  • 19
    Faiola S, Tsoi E, Huggon IC, Allan LD, Nicolaides KH. Likelihood ratio for trisomy 21 in fetuses with tricuspid regurgitation at the 11 to 13 + 6-week scan. Ultrasound Obstet Gynecol 2005; 26: 2227.