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Ethical Issues in First-Trimester Screening
S. Chasen, D. Skupski, L. McCullough* and F. Chervenak
Weill Medical College of Cornell University, Department of Obstetrics and Gynecology,
New York, NY, U.S.A.
*Center for Medical Ethics and Health Policy, Baylor College of Medicine, Houston, TX,
U.S.A.
Summary
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.
Introduction
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
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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 normalappearing 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 firsttrimester 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 noninvestigational 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
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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
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 FMFdocumented 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.
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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.
Conclusion
First-trimester screening performed according to accepted standards of
quality is a reliable diagnostic screen. There is no compelling beneficencebased 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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