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Volume 341:461-467 August 12, 1999 Number 7 Next

Abstract PDF Editorial by Copel, J. A. Letters Add to Personal Archive Add to Citation Manager Notify a Friend E-mail When Cited Related Article by Jenkins, T. M. PubMed Citation

ABSTRACT

Background Both first-trimester screening and second-trimester screening for Down's syndrome are effective means of selecting women for chorionic-villus sampling or amniocentesis, but there is uncertainty about which screening method should be used in practice. We propose a new screening method in which measurements obtained during both trimesters are integrated to provide a single estimate of a woman's risk of having a pregnancy affected by Down's syndrome.

Methods We used data from published studies of various screening methods employed during the first and second trimesters. The first-trimester screening consisted of measurement of serum pregnancy-associated plasma protein A in 77 pregnancies affected by Down's syndrome and 383 unaffected pregnancies and measurements of nuchal translucency obtained by ultrasonography in 326 affected and 95,476 unaffected pregnancies. The second-trimester tests were various combinations of measurements of serum alpha-fetoprotein, unconjugated estriol, human chorionic gonadotropin, and inhibin A in 77 affected and 385 unaffected pregnancies.

Results When we used a risk of 1 in 120 or greater as the cutoff to define a positive result on the integrated screening test, the rate of detection of Down's syndrome was 85 percent, with a false positive rate of 0.9 percent. To achieve the same rate of detection, current screening tests would have higher false positive rates (5 to 22 percent). If the integrated test were to replace the triple test (measurements of serum alpha-fetoprotein, unconjugated estriol, and human chorionic gonadotropin), currently used with a 5 percent false positive rate, for screening during the second trimester, the detection rate would be higher (85 percent vs. 69 percent), with a reduction of four fifths in the number of invasive diagnostic procedures and consequent losses of normal fetuses.

Conclusions The integrated test detects more cases of Down's syndrome with a much lower false positive rate than the best currently available test.

Screening for Down's syndrome in the second trimester of pregnancy, based on the concentrations of various markers in serum and maternal age, has become widely used in the past decade.^1,2 Down's syndrome is associated with low maternal serum alpha-fetoprotein and unconjugated estriol concentrations and high maternal serum human chorionic gonadotropin and inhibin A concentrations. Measurements of the first three markers, in addition to age, constitute the widely used triple test; measurements of all four (with age) make up the quadruple test.^2,3 In the first trimester, Down's syndrome is associated with high values for fetal nuchal translucency (measured by ultrasonography), high maternal serum concentrations of the free beta subunit of human chorionic gonadotropin, and low serum concentrations of pregnancy-associated plasma protein A. Nuchal translucency has been used either alone⁴ or in combination with the two serum markers (the combined test) in another screening protocol.⁵ Although the reliability of screening based on the serum markers is high, there is uncertainty about the reliability of the measurement of nuchal translucency; this uncertainty has led to debate about whether testing during the first trimester or the second is preferable.^{6,7,8,9,10,11}

With the current tests, 5 percent or more of screened women need to undergo amniocentesis in order for 60 to 80 percent of fetuses with Down's syndrome to be detected. Most women with positive screening tests have unaffected pregnancies. The false positive results, however, cause considerable anxiety, and about 0.9 in 100 women who undergo amniocentesis during the second trimester and 1.4 in 100 who undergo chorionic-villus sampling during the first trimester have miscarriages.² A screening test that had a rate of detection similar to those of the current tests but a markedly reduced rate of false positive results — thereby reducing the need for invasive diagnostic procedures — would be of great benefit. We evaluated a new screening method, which we call the "integrated test," that is designed to achieve this goal by integrating measurements of first- and second-trimester markers into a single test.

Methods

We estimated the performance of prenatal screening for Down's syndrome on the basis of maternal age combined with published data on the distribution of several first- and second-trimester markers in pregnancies affected by and those not affected by Down's syndrome, as confirmed subsequently by chorionic-villus sampling, amniocentesis, or postnatal assessment. The estimates of the performance of first-trimester screening (at 10 to 13 weeks) were based on measurements of nuchal translucency in 326 fetuses affected by Down's syndrome^4,5 and 95,476 unaffected fetuses^5,12 and on measurements of serum pregnancy-associated plasma protein A and the free beta subunit of human chorionic gonadotropin in 77 affected pregnancies and 383 unaffected pregnancies.¹³ These estimates were corrected for the overestimation of the rate of detection by the measurement of nuchal translucency⁴ that resulted from the termination of pregnancies that would otherwise have ended in miscarriage.⁸ We did not, however, take into account the possibility that fetuses with Down's syndrome that is detected by screening are more likely to be aborted spontaneously than unaffected fetuses.

The estimates of the performance of second-trimester screening (at 14 to 22 weeks) were based on measurements of serum alpha-fetoprotein, unconjugated estriol, human chorionic gonadotropin, and inhibin A in a different study of 77 pregnancies affected by Down's syndrome and 385 unaffected pregnancies; these measurements were made on serum samples stored before first-trimester serum or ultrasound screening was introduced.^14,15,16 The estimates of screening performance were modified on the basis of data on the improvement in determining the length of gestation with ultrasonography.¹⁷

The integrated test combines markers measured during both of the first two trimesters. The serum free beta subunit of human chorionic gonadotropin during the first trimester was excluded as a marker of Down's syndrome because of its expected high degree of correlation with serum total human chorionic gonadotropin during the second trimester. The results were similar when values for serum free beta subunit of human chorionic gonadotropin were included and those for serum total human chorionic gonadotropin were excluded.

All markers were expressed as multiples of the normal median for women with unaffected pregnancies at a given gestational age. A multivariate Gaussian model was fitted to the data on first-trimester and second-trimester markers in the affected and unaffected pregnancies, and the likelihood ratio was calculated. This ratio was used to adjust the risk of having a pregnancy at a particular maternal age that, in the absence of screening, would result in a live-born infant with Down's syndrome. In Bayesian terms, the likelihood ratio was multiplied by the prior odds to calculate the posterior odds. The detailed methods of the calculation of multiples of the normal median and estimation of the statistical parameters used in the multivariate Gaussian distributions have been described previously,^1,17 and the method of risk estimation has been empirically validated.¹⁸ The statistical parameters required to calculate the performance of the screening test have been reported previously.^{12,13,14,15,16} They include the coefficients for the correlation between markers within the same trimester, which are estimated separately in affected and normal pregnancies. Values for nuchal translucency and serum pregnancy-associated plasma protein A were not correlated with the second-trimester markers,^19,20 a finding consistent with the absence of an association in the first trimester between the values for nuchal translucency and serum free beta subunit of human chorionic gonadotropin^21,22,23 and between the values for serum pregnancy-associated plasma protein A and those for other serum markers.¹³

We compared the performance of the integrated test in screening for Down's syndrome with that of the first-trimester and second-trimester screening tests by examining the detection rates for specified false positive rates and the false positive rates for specified detection rates of each test. The detection rate is the proportion of affected pregnancies with a positive test result, also called sensitivity; the false positive rate is the proportion of unaffected pregnancies with a positive result, equivalent to 1 minus the specificity. The methods used to estimate the risk of Down's syndrome and the performance of screening have been described in detail elsewhere.^24,25 Estimates of the number of unaffected fetuses that were lost as a result of amniocentesis or chorionic-villus sampling were obtained from a review of randomized trials (which produced values of 0.9 percent and 1.4 percent, respectively).²

Results

The performance of second-trimester screening alone, first-trimester screening alone, and the integrated test that incorporated measurements from both trimesters is shown in Table 1. At a 5 percent false positive rate, the estimated rate of detection with the integrated test was 94 percent, greater than that with the most effective second-trimester test (quadruple test, 76 percent) or first-trimester test (combined test, 85 percent). At a 1 percent false positive rate, the estimated rate of detection for the integrated test was 85 percent (54 percent and 72 percent for the quadruple and combined tests, respectively). The integrated test detected at least as many affected pregnancies at a 1 percent false positive rate as either first-trimester or second-trimester screening alone at a 5 percent false positive rate. The extent to which the integrated test is better than the best first-trimester or second-trimester test (the combined test and the quadruple test, respectively) and the triple test is shown in Figure 1. At a 1 percent false positive rate, the rate of detection was 85 percent, as compared with 46 percent for the triple test. The steep early rise in the rate of detection with the integrated test reflects both high rates of detection and low rates of false positive results.

View this table: [in this window] [in a new window]   Table 1. Rates of Detection of Down's Syndrome at Specified False Positive Rates and False Positive Rates at Specified Detection Rates, According to the Type of Screening Test.

 

View larger version (7K): [in this window] [in a new window]   Figure 1. Rates of Detection of Down's Syndrome and False Positive Rates for Various Screening Tests. The triple test includes measurements of serum alpha-fetoprotein, unconjugated estriol, and human chorionic gonadotropin in the second trimester. The quadruple test includes measurements of serum alpha-fetoprotein, unconjugated estriol, human chorionic gonadotropin, and inhibin A in the second trimester. The combined test includes measurements of serum pregnancy-associated plasma protein A, free beta subunit of human chorionic gonadotropin, and nuchal translucency in the first trimester. The integrated test includes measurements of serum pregnancy-associated plasma protein A and nuchal translucency in the first trimester and measurements of serum alpha-fetoprotein, unconjugated estriol, human chorionic gonadotropin, and inhibin A in the second trimester.

 
Table 2 shows the performance of the integrated test without the measurement of nuchal translucency (because some centers may not have experience with this procedure) and serum inhibin A values (because some centers may not use this marker). Despite the loss of performance, a comparison of the data in Table 1 and Table 2 shows that if the measurement of either nuchal translucency or serum inhibin A were omitted it would still be of benefit to integrate first- and second-trimester markers into a single screening test. If it is not possible to measure nuchal translucency, ultrasonography should still be used to date the pregnancy — by measuring, for example, crown–rump length — in order to maximize the performance of the integrated screening test (since the serum concentration of pregnancy-associated plasma protein A increases by about 35 percent per week during the first trimester).

View this table: [in this window] [in a new window]   Table 2. Rates of Detection of Down's Syndrome at Specified False Positive Rates and False Positive Rates at Specified Detection Rates for the Integrated Test and Three Variations.

 
The percentages of screened women who would require an invasive diagnostic procedure and karyotypic analysis in order for 80 percent of pregnancies affected by Down's syndrome to be detected are shown in Figure 2, according to the screening test used. The percentage is the positive rate, including both true and false positives, in the numerator and all pregnancies screened in the denominator. The percentages decreased from 22.2 percent with the double test to 1 percent with the integrated test. For each test, Table 3 shows the risk cutoff needed to achieve a detection rate of 85 percent, and the estimated odds of an affected infant's being born for women with a positive result. The odds (the ratio of the number affected to the number unaffected) for the integrated test is 1:9, much higher than that for the first-trimester combined test (1:45) or for the best second-trimester test (1:88). There was also a substantial reduction in the number of unaffected fetuses lost as a result of amniocentesis or chorionic-villus sampling; 8 unaffected fetuses would have been lost per 100 pregnancies found by the integrated test to be affected, as compared with 61 per 100 and 79 per 100 with the best first-trimester and second-trimester tests, respectively.

View larger version (8K): [in this window] [in a new window]   Figure 2. Percentage of Screened Women Who Would Need to Undergo Amniocentesis or Chorionic-Villus Sampling in Order for 80 Percent of the Pregnancies Affected by Down's Syndrome to Be Detected, According to Type of Screening Test. The double test includes measurements of serum alpha-fetoprotein and human chorionic gonadotropin in the second trimester. The triple test includes measurements of serum alpha-fetoprotein, unconjugated estriol, and human chorionic gonadotropin in the second trimester. The quadruple test includes measurements of serum alpha-fetoprotein, unconjugated estriol, human chorionic gonadotropin, and inhibin A. The combined test includes measurements of serum pregnancy-associated plasma protein A, the free beta subunit of human chorionic gonadotropin, and nuchal translucency in the first trimester. The integrated test includes measurements of serum pregnancy-associated plasma protein A and nuchal translucency in the first trimester and serum alpha-fetoprotein, unconjugated estriol, human chorionic gonadotropin, and inhibin A in the second trimester.

 

View this table: [in this window] [in a new window]   Table 3. Odds of Delivering an Infant with Down's Syndrome at Term among Women with Positive Tests and Numbers of Procedure-Related Losses of Unaffected Fetuses According to the Screening Test Used.

 
To achieve a detection rate of 85 percent with the integrated test, the risk cutoff would be set at 1 in 120 (Table 3), a level at which the false positive rate would be 0.9 percent. Using the best test in the second trimester (the quadruple test) or in the first trimester (the combined test), a much lower cutoff (1 in 630 or 1 in 540, respectively) would be needed to achieve a similar detection rate, and the false positive rates would be much higher (9.8 percent and 4.9 percent). At a 5 percent false positive rate, the detection rate of the integrated test would be 94 percent, but the risk cutoff required to achieve this rate (1 in 940) may be regarded as too low to be clinically acceptable.

The reduction in the false positive rate with the integrated test is particularly evident for older women (Table 4). Among women 35 years of age or older, the false positive rate of the integrated test was only 3.3 percent (with a risk cutoff of 1 in 120), as compared with 19 percent for the triple test (with the usual risk cutoff of 1 in 250), with a gain in detection (92 percent vs. 88 percent). For every 100,000 women 35 years of age or older who were screened, only 30 unaffected fetuses would be lost because of diagnostic procedures with the integrated test, as compared with 171 with the triple test.

View this table: [in this window] [in a new window]   Table 4. Rates of Detection of Down's Syndrome and False Positive Rates According to Maternal Age and Screening Test.

 
Discussion

Prenatal screening for Down's syndrome is usually performed by testing of maternal serum when the woman is between 14 and 22 weeks pregnant. Depending on the serum markers used, this method yields detection rates of 59 to 76 percent at a false positive rate of 5 percent; the combination of serum testing and ultrasonography at 10 to 13 weeks yields a detection rate of about 85 percent with a false positive rate of 5 percent (Table 1). The integrated test can achieve a similarly high detection rate but at a much lower false positive rate (0.9 percent). Consequently the need for amniocentesis or chorionic-villus sampling is reduced by four fifths, with a similar reduction in the loss of unaffected fetuses. The fact that the results of screening would not be available for an additional few weeks may be seen as a disadvantage, but any such disadvantage is outweighed by the substantial increase in safety.

The estimates presented here are based on direct observations in large studies of first-trimester and second-trimester screening and validated statistical methods. Among women in established screening programs, who were grouped according to their level of risk as determined by the triple or quadruple test, the predicted risk in each group was close to the observed prevalence of Down's syndrome.^18,26,27 Because the same method of risk estimation was used to calculate the screening performance of the integrated test and because it was based on similar numbers of affected pregnancies, there is no reason to believe that our estimates of performance for the integrated test are any less valid than those for the tests currently available.

The integrated test takes advantage of the fact that different screening markers discriminate between the presence and absence of Down's syndrome at different times in pregnancy. For example, measurements of serum pregnancy-associated plasma protein A are useful only before 14 weeks, and those of inhibin A only after 14 weeks.² The low false positive rate of the integrated test would not be possible if first-trimester and second-trimester screenings were conducted independently; also, confusion would arise from giving women different estimates of risk at different stages of pregnancy. We examined whether women with extreme values for positive first-trimester screening results (based on increased nuchal translucency and older maternal age, with or without low values for serum pregnancy-associated plasma protein A) had so high a risk that their fetuses were affected by Down's syndrome that a diagnostic test should be offered without waiting to carry out tests in the second trimester. This was not the case; even a high initial risk estimate may be substantially reduced and the screening result may become negative with the integrated test.

An indication of the effectiveness of screening and prenatal diagnosis with the integrated test is shown in Table 1 and Table 3. For example, at an 85 percent rate of detection, the use of the integrated test instead of the triple test would obviate the need for amniocentesis in 13.6 of every 100 women with unaffected pregnancies (a false positive rate of 14.5 minus a rate of 0.9). The triple test is usually used with a 5 percent false positive rate; the integrated test with a cutoff of 1 in 120 would detect more affected pregnancies (85 percent vs. 59 percent) and would have only about one fifth the proportion of false positive results (0.9 percent vs. 5 percent).

The integrated test, through the use of information collected during both trimesters, makes screening and prenatal diagnosis much safer and more effective than other methods currently available. There is a further advantage over first-trimester screening alone in that amniocentesis, which is somewhat more accurate and safer than chorionic-villus sampling,² would be the diagnostic test used. Implementation of the integrated test would require that women seek prenatal care between 10 and 13 weeks of gestation and return within 5 weeks.

In the United States, the use of the integrated test instead of the triple test for prenatal screening for Down's syndrome would detect about 800 more affected pregnancies and save about 1400 unaffected fetuses from being lost as a result of amniocentesis or chorionic-villus sampling each year if all women identified as being at high risk underwent either of these diagnostic tests (the numbers would be proportionately lower if fewer women elected to be tested). In England and Wales, the corresponding numbers would be about 160 and 280.

Source Information

From the Department of Environmental and Preventive Medicine, Wolfson Institute of Preventive Medicine, St. Bartholomew's and the Royal London School of Medicine and Dentistry, Charterhouse Sq., London EC1M 6BQ, United Kingdom, where reprints requests should be addressed to Dr. Wald.

References

1. Wald NJ, Cuckle HS, Densem JW, et al. Maternal serum screening for Down's syndrome in early pregnancy. BMJ 1988;297:883-887. [Erratum, BMJ 1988;297:1029.] 
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22. Brizot ML, Snijders RJM, Butler J, Bersinger NA, Nicolaides KH. Maternal serum hCG and fetal nuchal translucency thickness for the prediction of fetal trisomies in the first trimester of pregnancy. Br J Obstet Gynaecol 1995;102:127-132. [Medline]
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24. 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;94:387-402. [Medline]
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Abstract PDF Editorial by Copel, J. A. Letters Add to Personal Archive Add to Citation Manager Notify a Friend E-mail When Cited Related Article by Jenkins, T. M. PubMed Citation

Related Letters:

Integrated Screening for Down's Syndrome
Jenkins T. M., Wapner R. J., Reynolds T., Zimmermann R., Wright E., Malone F. D., D'Alton M. E., Berkowitz R. L., Wald N., Watt H., Hackshaw A., Copel J. A., Bahado-Singh R. O.
Extract | Full Text  
N Engl J Med 1999; 341:1935-1937, Dec 16, 1999. Correspondence

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