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2002 Selected Articles

First-trimester Ultrasonographic Screening for Aneuploidy
An Ethical Justification for Clinical Use

Stephen T. Chasen, MD; Daniel W. Skupski, MD;
Laurence B. McCullough, PhD; Frank A. Chervenak, MD

Ultrasonographic screening in pregnancy continues to be a matter of controversy. Second-trimester ultrasonographic screening has been debated for the past 20 years. Even today, the American College of Obstetricians and Gynecologists (ACOG) does not endorse it as a standard of care. Nonetheless, second-trimester ultrasonography is widely practiced. In 1989, two of the authors argued that "prenatal informed consent for sonogram be accepted as an indication for the prudent use of obstetric ultrasound performed by qualified personnel."¹ Based on the available data, the authors believe that this argument can be extended to the use of ultrasonographic screening for aneuploidy in the first trimester.

RELIABILITY

The term nuchal translucency (NT) refers to the ultrasonographic measurement of nuchal skin late in the first trimester. Redundant nuchal skin is a specific feature of newborns with Down syndrome, and has been noted with other autosomal trisomies and Turner syndrome.² Nuchal edema occurs in the fetus as well, and can be detected on ultrasonography. Ultrasonographic findings range from a slight thickening of nuchal skin to cystic hygromata—ie, congenital malformations in which dilated lymphatic channels form a soft-tissue mass, typically in the posterior neck.

An association between increased nuchal skin-fold thickness in the second trimester and Down syndrome was reported in 1985.³ Although this is a useful second-trimester marker, most fetuses with Down syndrome will have normal nuchal skin-fold thickness in the second trimester.⁴

After a link was described between first-trimester nuchal edema and aneuploidy in 1992,⁵ numerous studies noted increased NT in the majority of fetuses with Down syndrome between 10 and 14 weeks' gestation. Most early studies defined increased NT using a single cutoff, usually 3.0 mm.⁶ Although the use of a single cutoff can simplify the screening process, there is a problem in that NT also increases with gestational age in normal fetuses.⁷ Thus, the accuracy of NT measurement 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. At later gestational ages, more normal fetuses would meet the cutoff, and there would be a higher rate of false-positive results.

Another problem with ultrasonographic screening for aneuploidy in the first trimester concerns operator technique. Nuchal translucency must be measured with a fetus in the optimal position, with appropriate image magnification and caliper placement.⁸ Poor technique will lead to lower detection rates and higher false-positive results.

Finally, maternal age is a vital component in any screening test for Down syndrome. The baseline risk usually depends on maternal age, and the factor of adjustment is based on the findings of the screening test. If this baseline is not considered, women at vastly different degrees of risk may all be assigned the same level. For instance, an abnormal NT measurement in a patient with an age-related aneuploidy risk of 1 in 100 would have a 10-fold higher absolute risk of Down syndrome than a patient with identical ultrasonographic findings and an age-related risk of 1 in 1,000.⁷

Many studies evaluating NT screening for Down syndrome, including those performed in the United States, used single cutoffs without well-defined techniques, and did not consider maternal age. Not surprisingly, wide ranges of sensitivity and false-positive rates ensued.⁹

 

Figure 1.		Figure 2.
A euploid 12-week fetus with normal NT. A nasal bone is clearly visualized.		An 11-week fetus with trisomy 21 and abnormal NT.

In 1998, the Fetal Medicine Foundation (FMF) published the results of its multicenter study assessing NT screening for Down syndrome. More than 100,000 pregnancies were screened at 22 centers in the United Kingdom at 10 to 14 weeks' gestation. All participating centers had demonstrated proficiency in measuring NT. The criteria for an appropriate image were magnification such that the fetus occupied at least 75% of the image, ability to distinguish between the skin and the amnion, and ability to measure the maximum thickness of subcutaneous translucency between the skin and soft tissue overlying the cervical spine. Risks for Down syndrome were calculated based on crown-rump length (CRL), NT, and maternal age (Figures 1 and 2).⁸

The study screened 100,311 singleton pregnancies. Pre- or postnatal karyotype was obtained in 96,127 cases, or the birth of a normal-appearing child was documented. To determine the sensitivity of NT, a risk threshold of 1 in 300 was used. There was a risk estimate of 1 in 300 or more in 7,907 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

The FMF has since accredited many international sites. Centers must demonstrate expertise in measuring NT, and images from all sonographers must be submitted for review before software is provided for risk estimation. Annual audits of all data are required. Investigators outside the United Kingdom (including the authors' center) have all reported Down syndrome detection rates of approximately 80%, with false-positive rates of 7% to 13%—ie, similar to those in the large British multicenter study.10-15 Cuckle has estimated a 73% detection rate at a fixed 5% false-positive rate.¹⁶

The results were recently reported from a multicenter National Institute of Child Health and Human Development (NICHD) study evaluating NT and first-trimester biochemical screening in detecting Down syndrome.¹⁷ The standards and quality controls implemented at each of the 12 sites were identical to those used by the FMF. Detection rates exceeding 80% were noted using NT alone or in combination with biochemical screening. This NICHD study performed at multiple sites in the United States corroborates that assessment of NT in a quality setting is indeed a reliable screening test.

Figure 3.
A 12-week fetus with trisomy 21, abnormal NT, and an absent nasal bone.

The ultrasonographic finding of absence of the nasal bone has also been proposed as a means to enhance the specificity of first-trimester ultrasonographic screening for aneuploidy.¹⁸ The fetal profile was imaged in 701 fetuses considered at high risk for Down syndrome based on maternal age and NT. In 73% of fetuses with Down syndrome, the nasal bone could not be seen. The nasal bone was not visualized in only 0.5% of euploid fetuses. Based on these findings, it is possible that including examination of the fetal profile for the presence of the nasal bone could increase the sensitivity of first-trimester ultrasonographic screening for aneuploidy to 85%, and decrease the false-positive rate. The authors have noted absence of the nasal bone in aneuploid fetuses with increased NT (Figure 3), and are evaluating this prospectively.

In the authors' view, the FMF data reported from centers in many countries demonstrate that NT should be considered a reliable screen for Down syndrome only when performed in experienced hands with standards similar to those used in the FMF centers. Images must be obtained by experienced sonographers with standard techniques, and NT measurements should be assessed as a continuous variable. Maternal age must be considered in establishing risk. Finally, data must be audited periodically to ensure that quality standards are maintained.

While the authors believe that NT is reliable when performed in a quality setting, it cannot be considered the standard of care at this time. However, because data suggest that this test is reliable if performed with appropriate expertise, it is reasonable to offer it when quality screening is available. Only when expertise is widespread and there is agreement regarding cost efficiency and cost benefit, can NT be considered to be standard of care. Implementation of universal screening will require broad-based education of physicians, sonographers, patients, and insurers.

Currently, first-trimester sonographic and biochemical techniques for aneuploidy screening are being evaluated in prospective studies. It has been suggested that NT should not be used in a noninvestigational setting until data from these studies are available.¹⁹ The authors believe that, given the scientific rigor and the published results from many centers using FMF techniques, NT should not be considered investigational, but instead a highly reliable diagnostic screen when performed in expert hands meeting FMF criteria.

While the authors do not believe that further studies are necessary to confirm that NT is a reliable diagnostic screen, other important questions remain. The value of NT compared with biochemical screening and second-trimester ultrasonography, the ideal combination of tests in Down syndrome screening, and the natural history of the Down syndrome fetus with abnormal NT findings are investigational, and ongoing trials may provide important information in these areas.19 Nonetheless, investigation in these areas does not negate the established value of first-trimester ultrasonographic NT screening for aneuploidy, or preclude its use in a noninvestigational setting.

RISKVERSUS BENEFIT

Beneficence is a principle of medical ethics that obligates the physician to seek a preponderance of clinical good over clinical harm for patients. This is the oldest principle of medical ethics, and can be found throughout Western history from Hippocratic texts to contemporary bioethics. Applying beneficence to this subject requires an analysis of potential clinical benefits and harms.²⁰

If first-trimester screening for Down syndrome with NT 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. However, these women may choose to undergo invasive testing if there is evidence of an increased risk based on screening tests. One recent study suggests that the availability of NT screening may decrease the rate of invasive testing in high-risk women.21 Undergoing a combination of tests, including first-trimester ultrasonography as well as second-trimester serum screening, could increase the likelihood that a fetus with Down syndrome will be identified. In the future, it may be possible to integrate these and other tests to derive a single estimation of risk.²²

Other women are determined to undergo an invasive test to exclude the possibility of Down syndrome, but may use NT to assist them in choosing between amniocentesis and chorionic villus sampling (CVS). Although it is not clear that CVS has a higher complication rate than amniocentesis when performed by an experienced operator,²³ slightly higher miscarriage rates have been described with CVS.²⁴ Some women would prefer to avoid CVS and undergo amniocentesis for other reasons, including the small incidence of placental mosaicism found on CVS that requires subsequent amniocentesis, and the ability to screen for neural tube defects by determining amniotic fluid -fetoprotein (AFP) levels. If NT were to reveal a high risk of Down syndrome, however, many of these women may be willing to undergo CVS to achieve an earlier diagnosis.

Women considered to be at low risk may also be interested in first-trimester screening for Down syndrome. Informed patients are aware that women of any age can give birth to a child with Down syndrome, and may desire first-trimester screening to increase the detection rate. If a sensitive first-trimester test with a low false-positive rate is available, this is certainly a reasonable option, as these women could undergo invasive testing if NT findings are abnormal.

Finally, NT may be particularly beneficial for women with multifetal pregnancies. Second-trimester serum screening for Down syndrome, the current standard of care in singleton pregnancies, is not useful in multifetal pregnancies. Second-trimester ultrasonography can also be used to screen for Down syndrome, although investigators have questioned its utility because of high false-positive rates and unclear detection value. Thus, NT screening may be the only reliable test for Down syndrome in multifetal pregnancies, which could lead to the early diagnosis of aneuploidy. Women could then choose selective termination of an abnormal fetus at a relatively early gestational age.

 

Table 1. Potential Benefits of NT Screening Increased detection rates for aneuploidy in all patients Option for high-risk patients who may wish to avoid invasive testing Assist choice between amniocentesis and CVS Association of abnormal NT with major congenital abnormalities Accurate aneuploidy screening in multifetal pregnancies Other potential benefits of early ultrasonography More accurate gestational age assessment More accurate assessment of amnionicity and chorionicity in multifetal pregnancies Early diagnosis of major structural anomalies

Aside from screening for Down syndrome, ultrasonography performed to measure NT has other benefits. Increased NT is associated with other chromosomal and structural anomalies.²⁵ Accurate estimation of gestational age and identification of amnionicity and chorionicity in multifetal gestations are additional well-described benefits of first-trimester ultrasonography.²⁶ The potential benefits of ultrasonographic NT screening in the first trimester are summarized in Table 1.

The use of NT screening for Down syndrome also has the potential for harm, however. Obtaining this measurement requires meticulous attention to technique and failure could result in both false-positive and false-negative results. This can lead to higher rates of invasive testing and miscarriage if risks are overestimated, or women with affected pregnancies not undergoing prenatal diagnosis if risks are underestimated. Ongoing review of data and follow-up are essential to document the quality of screening.

 

Table 2. Potential Harms of NT Screening Poor technique or interpretation leading to inaccurate risk estimates Underestimation of risk leading to missed diagnosis Overestimation of risk leading to increased rate of invasive testing and higher rates of miscarriage Serial screening leading to higher cumulative false-positive rates, resulting in increased rates of invasive testing and miscarriage

It is also important to note that NT does not replace second-trimester serum screening, which should be performed even if NT 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 unnecessary invasive tests and lead to a higher rate of loss of normal fetuses. The potential risks of ultrasonographic NT screening are listed in Table 2.

In summary, it is not reasonable to conclude that the potential harm of NT screening outweighs the potential benefit when quality testing is available. In the authors' view, the potential benefits outweigh the potential risks.

PATIENT AUTONOMY

Respect for patient autonomy is a principle that obliges the physician to seek the balance of benefit over harm for the patient that is acceptable to the patient.²⁰ The relevance of respect for autonomy to NT screening is that first-trimester identification of fetuses at risk provides the opportunity for early prenatal testing and the subsequent option of early termination, which is important to many women.

The process of informed consent for NT screening should involve several stages.¹ Because NT 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 theoretical benefits of NT, 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 must be able to do. The physician should be prepared to discuss his or her evaluation of the available data regarding NT screening for Down syndrome.

After these steps, the pregnant woman should be allowed to articulate her preference regarding the use of NT to screen for Down syndrome in the first trimester. The physician can then make a recommendation. Finally, a thoughtful and sensitive discussion of any disagreement should ensue, after which the woman and her partner can make their decision. This process provides a significant role for the experience-based judgment of the physician while maintaining respect for the pregnant woman's autonomy.

It is important to note that the physician should offer the option of NT to a pregnant woman only if quality testing is available. As previously discussed, it is the responsibility of the physician to ensure that the center to which patients are referred for NT screening maintains acceptable standards. Without quality testing in experienced centers, the harms of screening may outweigh the benefits.

CONCLUSION

When conducted according to accepted standards of quality, first-trimester testing for NT is a reliable diagnostic screen. There is no compelling beneficence-based argument in opposition, and offering the test is an important autonomy-enhancing strategy. Such screening should be offered only in centers where high quality is available. In the authors' view, the results of ongoing trials will support this position.

Stephen T. Chasen, MD, is assistant professor of obstetrics and gynecology; Daniel W. Skupski, MD, is associate professor of obstetrics and gynecology; and Frank A. Chervenak, MD, is professor and chairman of the Department of Obstetrics and Gynecology at Weill Medical College of Cornell University in New York City, NY. Laurence B. McCullough, PhD, is professor of medicine and medical ethics at the Center for Medical Ethics and Health Policy at Baylor College of Medicine in Houston, Tex.

REFERENCES

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