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Chorionic-villus sampling in the first trimester and amniocentesis in the second trimester are equally effective and safe procedures with similar rates of procedure-induced loss at experienced centers.2,3 Total loss rates after chorionic-villus sampling are higher because of the higher rate of spontaneous abortion at the earlier gestational age when sampling is performed. The advantages of diagnostic testing in the first trimester are the inherently greater privacy at the time of the diagnosis and the greater safety of termination of the pregnancy (when desired) if the results are abnormal, as well as the earlier reassurance if the results are normal. The option of making the diagnosis in the first trimester is eliminated by combined first- and second-trimester screening.
A woman's approach to prenatal diagnosis is a personal one. Screening tests need to be sufficiently sensitive and specific to provide meaningful guidance, but a protocol that maximizes the results by delaying the diagnosis will not be satisfactory to most women. In a recent study of a first-trimester screening protocol involving the use of nuchal translucency and biochemical markers, the sensitivity for the detection of Down's syndrome was 89 percent, with a 5 percent false positive rate.4 The approach of informing women of the risks on the basis of the results of screening in the first trimester, although leading to a slightly higher frequency of invasive testing, allows a couple to choose immediate testing by chorionic-villus sampling or to await additional, noninvasive evaluation in the second trimester.
Thomas M. Jenkins, M.D.
Ronald J. Wapner, M.D.
Thomas Jefferson University
Philadelphia, PA 19107-5083
References
There is little reported evidence on sequential changes in maternal serum markers. A combination of first- and second-trimester results must be based on the assumption that markers that are abnormal in the first trimester will also be abnormal in the second trimester; conversely, normal markers will be normal in both trimesters. We studied 187 normal pregnant women in whom the duration of gestation was determined by ultrasonography at four-week intervals starting between day 45 and day 76 of gestation and ending between day 128 and day 180. At each visit, we measured serum pregnancy-associated plasma protein A, alpha-fetoprotein, unconjugated estriol, and total and free beta human chorionic gonadotropin. Despite adequate correction for gestational age on a population basis, we found that the multiple of the median value sometimes changed by as much as 1 and that in any one woman, the multiple of the median value could increase, decrease, increase and decrease, or remain roughly constant during gestation. Therefore, risk estimates calculated at different times varied; depending on the combinations of tests used (with two or three analytes), the discordance rate ranged from 12.3 percent to 25.7 percent. The effect of combining two biochemical measurements and one ultrasound measurement in the first trimester with four biochemical measurements in the second trimester cannot be estimated.
Consequently, we believe it is impossible to design a multistage test with the use of population-based values from independent assessments in different trimesters. Furthermore, it is impossible to estimate the benefits of such a test — that is, whether it will identify more cases of Down's syndrome or will simply increase the false positive rate with no actual diagnostic gain.
Tim Reynolds, M.D.
Queen's Hospital
Burton-on-Trent, Staffordshire DE13 0RB, United Kingdom
Roland Zimmermann, M.D.
University Hospital of Zurich
Zurich 80066, Switzerland
Eileen Wright, Ph.D.
University of Strathclyde
Glasgow G1 1XL, United Kingdom
References
First-trimester screening for Down's syndrome with the use of measurements of nuchal translucency has been evaluated by several groups outside the United States. The rates of detection of Down's syndrome ranged from 29 percent to 91 percent.2 The results of first-trimester biochemical screening have been much more consistent with rates of detection ranging from 55 percent to 63 percent.3 However, the combination of first-trimester biochemical screening and measurement of nuchal translucency has never been subjected to rigorous evaluation in a single large group of pregnant women. After evaluating all the available data, the Committee on Genetics of the American College of Obstetricians and Gynecologists recently concluded that first-trimester measurement of nuchal translucency, with or without serum testing, remains an investigational procedure and is not recommended for routine clinical use.4
The editorial is confusing in that the authors initially state that the best way to combine screening tests should be determined by measurements in a single group of women, but they later say that they currently recommend both first- and second-trimester screening.1 What data are Copel and Bahado-Singh using to justify the implementation of such a combined method of screening? What criteria are they using to define an increased risk of Down's syndrome in the first trimester, and from what published data are such risks derived?
Until further data are available, we endorse the opinion of the American College of Obstetricians and Gynecologists and strongly caution physicians and patients that combined first-trimester screening should not be performed or acted on in clinical practice apart from research protocols. The standard of care in the United States for screening for Down's syndrome continues to be measurements of multiple serum markers in the second trimester, with consideration of maternal age.
Fergal D. Malone, M.D.
Mary E. D'Alton, M.D.
Columbia University College of Physicians and Surgeons
New York, NY 10032-3784
Richard L. Berkowitz, M.D.
Mount Sinai School of Medicine
New York, NY 10029-6574
References
To the Editor: Jenkins and Wapner question the size of the studies used in our analysis. We used three principal data sets, each based on at least 77 pregnancies with Down's syndrome, from a total of about 150,000 pregnancies. Jenkins and Wapner are correct in suggesting that, all other things being equal, offering a screening test for Down's syndrome early in pregnancy is better than offering one later. But all things are not equal. The integrated test is considerably better than first-trimester screening alone. With the same detection rate of 85 percent, there is about an 80 percent reduction in the false positive rate and therefore an 80 percent reduction in the loss of unaffected fetuses even if, as judged by Jenkins and Wapner, chorionic-villus sampling and amniocentesis are equally effective and safe.
Reynolds et al. express an unjustified concern about screening methods. Their criticisms of first-trimester biochemical screening were addressed,1 and the estimates from other studies of first-trimester biochemical screening were similar to ours.2 We used data on nuchal translucency and Down's syndrome that were reported by Nicolaides et al.3 — data that Reynolds et al. cite in their letter and thus accept as authoritative. Other studies indicate that our estimates of the performance of screening in the first trimester, with the combined use of biochemical measurements and nuchal translucency, are accurate.4,5 The integrated test is not based on the assumption that markers that are abnormal in the first trimester will also be abnormal in the second trimester. The strength of the integrated test rests on the fact that this is not the case.
We agree with Malone et al. that the results of screening with measurements of nuchal translucency have been variable, largely because of variations in the accuracy of the measurement.
The potential value of the integrated test in increasing the effectiveness of screening, particularly by reducing the associated anxiety and fetal loss, is large and should not be lost sight of in discussions about the different components of the test.
Unfortunately, there was an editorial error in our article. The error concerns Figure 2, which shows the percentage of women screened who would need to undergo amniocentesis or chorionic-villus sampling in order for 85 percent of the pregnancies affected by Down's syndrome to be detected. In the figure as printed, 80 percent appears instead of 85 percent. The error was made on the vertical axis of the figure, in the figure title, and in the 10th line in the right-hand column on page 464.
Nicholas Wald, F.R.C.P., D.Sc.
Hilary Watt, M.Sc.
Allan Hackshaw, M.Sc.
Wolfson Institute of Preventive Medicine
London EC1M 6BQ, United Kingdom
References
The question at hand is what to do during the two to four years it will take to confirm or refute the existing reports. We believe that with the reported high correlation between abnormal nuchal translucency and Down's syndrome and the preponderance of studies supporting this claim, it is legitimate to discuss this test and to offer it to interested couples.
Joshua A. Copel, M.D.
Ray O. Bahado-Singh, M.D.
Yale University School of Medicine
New Haven, CT 06520-8063
References
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