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It has previously been argued that “prenatal informed consent for sonogram be accepted as an indication for the prudent use of obstetric ultrasonography performed by qualified personnel.” We extend this argument to the use of ultrasound screening for aneuploidy in the first trimester.
It has previously been argued that “prenatal informed consent for sonogram be accepted as an indication for the prudent use of obstetric ultrasonography performed by qualified personnel.”1 We extend this argument to the use of ultrasound screening for aneuploidy in the first trimester.
A specific feature of newborns with Down syndrome is redundant nuchal skin. This has also been noted with other autosomal trisomies, as well as Turner syndrome.2 Benacerraf et al. have reported an association between increased nuchal skin fold thickness in the second trimester and Down syndrome.3 Though this is a useful second-trimester marker for Down syndrome, most fetuses with Down syndrome will have normal nuchal skin fold thickness4 in the second trimester. Nicolaides et al. have described an association between first-trimester nuchal edema and aneuploidy.5 Numerous studies subsequently described increased nuchal translucency in the majority of fetuses with Down syndrome between 10 and 14 weeks. Most early studies defined increased nuchal translucency using a single cutoff, usually 3.0-mm.6 Although use of a single cutoff can simplify the screening process, a problem with using a cutoff in defining abnormal nuchal translucency is the fact that nuchal translucency increases with gestational age in normal fetuses.7 Thus, the accuracy of nuchal translucency would vary based on gestational age. At earlier gestational ages, fewer fetuses with Down syndrome would meet this cutoff, and there would be a higher rate of false-negative results. Another problem with ultrasound screening for aneuploidy in the first-trimester concerns operator technique. If appropriate techniques are not used, lower detection rates and higher false-positive results will be seen.8 Maternal age is a vital component in any screening test for Down syndrome. The baseline risk is usually based on maternal age, and the factor of adjustment is based on the findings of the screening test. If baseline risk is not considered, women at vastly different levels of risk may be assigned the same level of risk.7
Many studies evaluating nuchal translucency screening for Down syndrome, including those performed in the United States, were performed using single cutoffs, without well-defined techniques, and did not consider maternal age. Not surprisingly, wide ranges of sensitivity and false-positive rates have been described.9
The Fetal Medicine Foundation (FMF) study assessed nuchal translucency screening in over 100,000 pregnancies at 22 centers in the United Kingdom from 10-14 weeks. Risks for Down syndrome were calculated based on crown-rump length, nuchal translucency, and maternal age.8 In 96,127 cases, prenatal or postnatal karyotype was obtained, or a birth of a normal-appearing child was documented. To determine sensitivity of nuchal translucency, a risk threshold of 1 in 300 was used. There was a risk estimate of 1 in 300 or more in 7907 normal fetuses (8.3%), in 268 of 326 fetuses with Down syndrome (82.2%), and 253 of 325 fetuses with other chromosomal abnormalities (77.9%).8 Investigators outside the United Kingdom, including our center, have all reported Down syndrome detection rates of approximately 80%, with false positive rates of 7-13%, similar to those in the large multicenter study in the United Kingdom.10-15
The results from a NICHD funded study evaluating NT and first trimester biochemical screening in detecting Down syndrome were recently reported.16 The standards and quality controls implemented at each of 12 sites were identical to those of the FMF. Detection rates over 80% using NT alone or in combination with biochemical screening were described. This NICHD study performed in multiple sites in the United States corroborates that NT performed in a quality setting is indeed a reliable screening test.
Nicolaides and colleagues recently described the ultrasound finding of absence of the nasal bone as a means to enhance the specificity of first-trimester ultrasound.17 Based on these findings, it is possible that inclusion of examination of the fetal profile for the presence or absence of the nasal bone could increase the sensitivity to 85% and decrease the false-positive rate of first-trimester ultrasound screening for aneuploidy. In our view, the FMF data reported from centers in many countries demonstrate that nuchal translucency should be considered a reliable screen for Down syndrome only when performed in experienced hands with standards similar to those used in FMF centers. While we believe that nuchal translucency is reliable when performed in a quality setting, it cannot be considered the standard of care at this time.
Currently, first-trimester sonographic and biochemical techniques of aneuploidy screening are being evaluated in prospective studies. It has been suggested that nuchal translucency should not be used in a non-investigational setting, until data from these studies are available.18 We believe that, given the scientific rigor and the published results from many centers using FMF techniques, nuchal translucency should not be considered investigational, but instead a highly reliable diagnostic screen when performed in expert hands meeting FMF quality controls.
While we do not believe that further studies are necessary to confirm that nuchal translucency is a reliable diagnostic screen, other important questions remain. The comparative value of nuchal translucency to biochemical screening and second-trimester ultrasound, the ideal combination of tests in Down syndrome screening, and the natural history of the Down syndrome fetus with abnormal nuchal translucency are investigational, and ongoing trials may provide important information in these areas.18
Ethical issues mainly concern benefits and risks and the implications of respect for autonomy.19 If first-trimester screening for Down syndrome with nuchal translucency is available at a specialized center with FMF-documented expertise, patients may benefit in several ways. Many women at high-risk would prefer to avoid invasive testing, because of the risk of miscarriage. One recent study suggests that the availability of nuchal translucency screening may decrease the rate of invasive testing in high-risk women.20 Undergoing a combination of tests, including first-trimester ultrasound as well as second-trimester serum screening, could increase the likelihood that a fetus with Down syndrome will be identified. In the future, we may have the ability to integrate these and other tests to derive a single estimation of risk.21
Other women are determined to undergo either an invasive test to exclude the possibility of Down syndrome, but may use nuchal translucency to assist them in choosing between amniocentesis and CVS. Although it is not clear that CVS, when performed by an experienced operator, has a higher complication rate than amniocentesis,22 slightly higher miscarriage rates have been described with CVS.23 Some women would prefer to avoid CVS and undergo amniocentesis for other reasons. These include the small incidence of placental mosaicism found on CVS, which requires amniocentesis to be performed subsequently, and the ability to screen for neural tube defects by determining amniotic fluid AFP. If nuchal translucency were to reveal a high risk of Down syndrome, however, these women would be willing to undergo CVS to achieve an earlier diagnosis.
Nuchal translucency may be beneficial for women with multifetal pregnancies. Nuchal translucency screening may be the only reliable screening test for Down syndrome in multifetal pregnancies, and could lead to the early diagnosis of aneuploidy. Women could then choose selective termination of an abnormal fetus at a relatively early gestational age. Aside from screening for Down syndrome, ultrasound has other benefits. Increased nuchal translucency is associated with other chromosomal abnormalities as well as many structural anomalies.
Nuchal translucency screening has the potential to harm. Obtaining this measurement requires meticulous attention to technique; failure to do so could lead to both false-positive and false-negative results. It is also important to note that nuchal translucency does not replace second-trimester serum screening, which should be performed if nuchal translucency testing reveals a low risk of Down syndrome. Until different screening tests can be integrated to derive a single estimation of risk, it is important that women be aware that serial screening will result in higher cumulative false-positive rates. This could increase the number of invasive tests performed, and lead to a higher rate of loss of normal fetuses. We conclude that the potential benefits outweigh the potential harms when quality testing is available.
Respect for autonomy is implemented clinically in the informed consent process,19 which should involve several stages.1 Since nuchal translucency screening must be done before 14 weeks’ gestation, the physician should discuss this test with the pregnant woman at the first prenatal visit. Information should be provided about the actual and theoretic benefits of nuchal translucency, including potential benefits and harms. The pregnant woman should evaluate this information in terms of her own values and beliefs; this is something every autonomous patient is able to do. The physician should be prepared to discuss his or her evaluation of available data regarding nuchal translucency screening for Down syndrome. After these steps, the pregnant woman should be able to articulate her preference regarding the use of nuchal translucency to screen for Down syndrome in the first-trimester.
First-trimester screening performed according to accepted standards of quality is a reliable diagnostic screen. There is no compelling beneficence-based argument opposed to offering it, and offering it is an important autonomy-enhancing strategy. Such screening should be offered only in centers where high quality is available.
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