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NEJM
 Editorial

Volume 349:1471-1473 October 9, 2003 Number 15

Screening for Down's Syndrome � Too Many Choices?
Michael T. Mennuti, M.D., and Deborah A. Driscoll, M.D.

An increased risk of fetal Down's syndrome (trisomy 21) is the most common reason for offering prenatal genetic diagnosis. The chance of giving birth to a child with Down's syndrome increases throughout a woman's reproductive years. Since the 1970s, an age of 35 years at delivery has been used as the cutoff for offering amniocentesis for this indication in the United States. After this age, the risk of Down's syndrome rises rapidly and is thought to balance the risks of amniocentesis. Nondirective counseling enables couples to compare the risk and burden of Down's syndrome with the risks, accuracy, and limitations of amniocentesis. Numerical risks cannot be compared in a straightforward manner but are strongly influenced by the possible outcomes and a couple's personal values. Although always complex, the decision-making process was easier when only one test was available rather than the array of choices women have today.

The majority of children with Down's syndrome are born to women who are younger than 35 years old. The identification of younger women with an increased risk became possible after Merkatz et al. reported an association between a low alpha-fetoprotein level and fetal aneuploidy,1 launching an era of maternal serum screening to assess the risk of fetal Down's syndrome. Subsequent studies showed that the maternal serum levels of three markers � alpha-fetoprotein, {beta} human chorionic gonadotropin, and unconjugated estriol � between 15 and 22 weeks of gestation can be used to adjust the risk based on maternal age alone.2 A screening test for Down's syndrome is considered positive if the second-trimester risk is at least 1 in 270 pregnancies. The frequency of positive tests varies with the age of the population but is generally less than 5 percent. The sensitivity is 60 to 70 percent. The recent addition of a fourth marker, inhibin A, increases the sensitivity to 75 percent (95 percent confidence interval, 66 to 84).3

Some women undergo chorionic-villus sampling during the first trimester rather than screening or amniocentesis during the second trimester. Some women, such as those carrying multiple fetuses, are not candidates for second-trimester serum screening. Others decline screening because they do not wish to undergo prenatal diagnosis or would not consider pregnancy termination on the basis of the results. The anxiety experienced by friends or relatives who had a positive screening test followed by normal findings on amniocentesis deters some women from undergoing screening. It has been suggested that serum screening would be a more cost-effective approach than maternal age.4 Women who are 35 years of age or older increasingly opt to undergo serum screening and ultrasonography before deciding about amniocentesis. Obstetricians and patients have learned to deal with a quantitative screening test that has less-than-ideal sensitivity and the anxiety that follows a positive result.

With the emergence of alternative approaches earlier in pregnancy, decisions about screening are becoming more complex. Studies in the 1990s showed an association between Down's syndrome and increased nuchal translucency, a sonolucent space evident at the back of the fetus's neck in the first trimester. In 1995, Wald et al. demonstrated the feasibility of first-trimester serum screening for Down's syndrome.5

In this issue of the Journal, Wapner et al. report their experience with first-trimester screening for Down's syndrome and trisomy 18 between 74 and 97 days of gestation.6 They used the maternal serum levels of free {beta} human chorionic gonadotropin and pregnancy-associated plasma protein A and ultrasonographic measurement of fetal nuchal translucency to adjust the maternal-age�related risk of Down's syndrome and trisomy 18. At a cutoff of 1:270, the rate of detection of Down's syndrome was 85.2 percent, with a 9.4 percent rate of positive screening results. At a positive rate of 5 percent, the risk was 1:129 and the sensitivity was 78.7 percent (95 percent confidence interval, 66.3 to 88.1), which are similar to the results of other studies of first-trimester screening.7,8,9

The results of this multicenter study in the United States contribute to the evolving story of first-trimester screening. Women with positive results on first-trimester screening have the option of chorionic-villus sampling. As mentioned by Wapner et al., early diagnosis allows women greater privacy and safer termination of affected pregnancies. However, there is a slightly higher risk of pregnancy loss with chorionic-villus sampling than with second-trimester amniocentesis.10,11 Only half the women who elected to terminate the pregnancy in the study by Wapner et al. did so before 16 weeks of gestation. Thus, it is not clear how often women who undergo first-trimester screening will realize the benefits ascribed to this approach.

Should first-trimester screening become another option offered to women who seek early prenatal care? Although the sensitivity of first-trimester screening was higher in the current study and in some others that have been reported, the confidence intervals overlap the sensitivity of second-trimester screening involving the measurement of four serum markers. First-trimester screening is likely to appear to be more sensitive than second-trimester screening because there is a higher prevalence of Down's syndrome in the first trimester. Wapner et al. corrected for this by using published rates of pregnancy loss involving fetuses with Down's syndrome.

The reliability of first-trimester screening is dependent not only on the quality control of the biochemical assays but also on the ultrasonographic measurements. The ability to obtain an accurate measurement of nuchal translucency depends on several factors, including the training and experience of the operator, body habitus of the patient, and fetal position. In some cases this measurement cannot be obtained. With the methods used by Wapner et al., measurements are converted to multiples of the median for gestational age, and a difference as small as 1/10 of a millimeter may mean the difference between a positive and a negative screening test. Variables such as resolution, magnification, and contrast may greatly affect the interobserver and intraobserver variability of measurements at this critical level. We are not told how the use of a dichotomous cutoff value for each week of gestation or the raw nuchal-translucency measurements would affect the sensitivity or the positive rate of screening. Before first-trimester screening can be offered in practice, guidelines for measuring and interpreting nuchal-translucency measurements and for quality control are needed.

Several other questions remain. An increase in nuchal translucency has been observed in association with other aneuploidies, heart defects, and certain genetic disorders. These associations deserve further evaluation. Will first-trimester measurement of nuchal translucency assume a broader role in early-pregnancy evaluation?

On the basis of published data, Wald et al. concluded that integrating the results of first- and second-trimester screening would be more sensitive and result in fewer diagnostic tests and fewer procedure-related losses of normal pregnancies than the use of either method alone.12 Would this approach better serve women? Would women with positive first-trimester screening tests await the results of second-trimester screening or opt for immediate diagnosis? Should we offer women who have negative results on first-trimester screening the option of second-trimester screening?

A multicenter trial nearing completion in the United States, which is much larger than the study by Wapner et al., is comparing first- and second-trimester screening in the same patient.13 This approach should correct for spontaneous losses of pregnancies involving Down's syndrome, provide information regarding the relative sensitivity of the two approaches, and allow an assessment of the value of integrating the results. It should also substantively add to the information provided by Wapner et al. and may answer some of our questions.

In the meantime, we believe that offering second-trimester screening should continue to be the standard of care. Obstetricians and ultrasonographers should not routinely implement first-trimester screening in clinical practice until there is sufficient information for the development of practice guidelines. In the future, first-trimester screening may become another option routinely offered to women who seek early prenatal care. The value of earlier, noninvasive diagnosis with the use of fetal cells from the maternal circulation14 or the endocervical canal15 is being investigated, and such an approach could eventually eliminate the need for screening. Until then, women may face an increasing array of complex choices.


Source Information

From the Divisions of Reproductive Genetics (M.T.M., D.A.D.) and Maternal Fetal Medicine (M.T.M.), Department of Obstetrics and Gynecology, University of Pennsylvania School of Medicine, Philadelphia.

References

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