Riverbend DS Assocation Home Page » Resources » Patents » Prenatal Screening » Method for Determining the Risk of Trisomy 21 in the Second Trimester Method for Determining the Risk of Trisomy 21 in the Second Trimester |
Inventors: Vintzileos; Anthony M. (Bridgewater, NJ); Egan; James F.X. (Longmeadow, MA) Assignee: University Of Medicine & Dentistry of NJ (Newark, NJ) Appl. No.: 507624 Filed: July 26, 1995 |
Primary Examiner: Manuel; George Attorney, Agent or Firm: Muccino; Richard R. United States Patent 5,622,176 April 22, 1997 |
Claims
We claim:
1. A method for the prenatal detection of trisomy 21
in the second trimester by fetal long bone biometry which comprises the steps
of:
(a) measuring ultrasonically the biparietal diameter and the length
of the femur, humerus, tibia, and fibula bones in fetuses of a patient
population in the second trimester;
(b) performing amniocentesis on the
patient population in step (a) to determine which fetuses are normal and which
fetuses have trisomy 21;
(c) from the normal fetuses, deriving equations
describing the predicted lengths of the femur, humerus, tibia, and fibula based
on the biparietal diameter measurements;
(d) calculating a ratio of
observed lengths to predicted lengths of the femur, humerus, tibia, and fibula
for all fetuses;
(e) comparing the ratios calculated in step (d) for
normal fetuses against the ratios calculated for fetuses having trisomy 21 and
determining a threshold, as a percentile of these ratios, for abnormally short
bone lengths in the fetuses having trisomy 21; and
(f) employing the
threshold determined in step (e) to detect prenatally trisomy 21 by fetal long
bone biometry.
2. The method according to claim 1, wherein step (c) is
performed with a computer software program.
3. The method according to
claim 1, wherein steps (d) is performed with a computer software program.
4. The method according to claim 1, wherein steps (e) is performed with
a computer software program.
5. A method for the prenatal detection of
trisomy 21 in the second trimester by adjusting the risk of trisomy 21 based on
fetal long bone biometry which comprises the steps of:
(a) measuring
ultrasonically the biparietal diameter and the length of the femur, humerus,
tibia, and fibula bones in fetuses of a patient population in the second
trimester;
(b) performing amniocentesis on the patient population in
step (a) to determine which fetuses are normal and which fetuses have trisomy
21;
(c) from the normal fetuses, deriving equations describing the
predicted lengths of the femur, humerus, tibia, and fibula based on the
biparietal diameter measurements;
(d) calculating a ratio of observed
lengths to predicted lengths of the femur, humerus, tibia, and fibula for all
fetuses;
(e) comparing the ratios calculated in step (d) for normal
fetuses against the ratios calculated for fetuses having trisomy 21 and
determining a threshold, as a percentile of these ratios, for abnormally short
bone lengths in the fetuses having trisomy 21;
(f) employing the
threshold determined in step (e) to determine sensitivity and specificity in
detecting prenatally trisomy 21 by fetal long bone biometry; and
(g)
employing the sensitivity and specificity determined in step (f) to adjust the
risk of trisomy 21.
6. The method according to claim 2, wherein step (c)
is performed with a computer software program.
7. The method according
to claim 2, wherein steps (d) is performed with a computer software program.
8. The method according to claim 2, wherein steps (e) is performed with
a computer software program.
9. The method according to claim 2, wherein
steps (f) is performed with a computer software program.
Description
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to a method for the prenatal detection of trisomy
21 in the second trimester by adjusting the risk of trisomy 21 based on fetal
long bone biometry. More particularly, this invention relates to (a) measuring
ultrasonically the biparietal diameter and the length of the femur, humerus,
tibia, and fibula bones in fetuses of a patient population in the second
trimester; (b) performing amniocentesis on the patient population in step (a) to
determine which fetuses are normal and which fetuses have trisomy 21; (c) from
the normal fetuses, deriving equations describing the predicted lengths of the
femur, humerus, tibia, and fibula based on the biparietal diameter measurements;
(d) calculating a ratio of observed lengths to predicted lengths of The femur,
humerus, tibia, and fibula for all fetuses; (e) comparing the ratios calculated
in step (d) for normal fetuses against the ratios calculated for fetuses having
trisomy 21 and determining a threshold, as a percentile of these ratios, for
abnormally short bone lengths in the fetuses having trisomy 21; and (f)
employing the threshold determined in step (e) to detect prenatally trisomy 21
by fetal long bone biometry. In another embodiment, the method comprises the
steps of (f) employing the threshold determined in step (e) to determine
sensitivity and specificity in detecting prenatally trisomy 21 by fetal long
bone biometry; and (g) employing the sensitivity and specificity determined in
step (f) to adjust the risk of trisomy 21.
2. Description of the
Background
The disclosures referred to herein to illustrate the
background of the invention and to provide additional detail with respect to its
practice are incorporated herein by reference. For convenience, the disclosures
are referenced in the following text and respectively grouped in the appended
bibliography.
Trisomy 21 (trisomy G, Down's syndrome, mongolism) is a
condition characterized by a small, anteroposteriorly flattened skull, short,
flat-bridged nose, epicanthal fold, short phalanges, and widened space between
the first and second digits of hands and feet, with moderate to severe
retardation, and associated with a chromosomal abnormality. In about 85% of
cases of trisomy 21, there is an extra chromosome 21. Typically, the affected
children are born to older mothers, but sporadic or trisomic mongolism may also
occur in children of young mothers. The overall incidence of trisomy 21 is about
1:700 live births, but there is a marked variability depending on maternal age.
In the early child-bearing years, the incidence of trisomy 21 is about 1:2000
live births whereas for mothers over 40, the incidence rises to about 45:1000
live births. Close to 50% of infants with trisomy 21 are born to mothers over
35. Nevertheless, recent studies have shown that the extra chromosome 21 can
occasionally come from the father.
The use of ultrasonography in the
prenatal detection of fetuses with trisomy 21 has been the subject of several
reports .sup.1-17. The combination of various ultrasound markers for trisomy 21
has increased the sensitivity to 83%-91% with relatively low false positive
rates ranging between 10% and 20% .sup.2,16. As a result, the use of ultrasound
to adjust the risk for trisomy 21 has been advocated, and therefore the need for
genetic amniocentesis in low as well as high risk patients .sup.16-17. In
general, this approach requires special expertise which has prevented the
incorporation of the "genetic" ultrasound into general practice. Although
specific expertise is not required for measuring the femur, humerus, renal
pelvis, or nuchal fold thickening, it is clear that expertise and experience are
required to assess hypoplasia of the middle phalanx of the fifth digit, wide
space between the first and second toe, and to diagnose structural
malformations, especially cardiac defects. Therefore, simplification of
sonographic detection of trisomy 21 would be desirable and would enhance the
clinical applicability. Although there are several accounts reporting that
fetuses with trisomy 21 are more likely to have short femur or humerus, there
are no reports regarding the usefulness of tibia and/or fibula measurements in
the prenatal detection of trisomy 21.
BRIEF DESCRIPTION OF THE FIGURE
AND TABLES
FIG. 1 illustrates the impact of ultrasound adjusted risk for
trisomy 21 in the general population.
Table I illustrates regression
equations for the expected long bone measurement (dependent variable) based on
the measured BPD (independent variable).
Table II illustrates abnormal
cut-off values of long bone measurements for a given BPD.
Table III
illustrates efficacy of long bone measurements alone and in combination in
detecting fetal trisomy 21.
Table IV illustrates long bone findings in
trisomy 21 fetuses.
Table V illustrates efficacy of fetal long bone
biometry to detect fetal trisomy 21 according to maternal age.
Table VI
illustrates midtrimester risk for trisomy 21 based on maternal age in a
structually normal fetus as modified by ultrasonic measurements of fetal long
bones.
Table VII illustrates midtrimester risk for trisomy 21 based on
triple screen in a structually normal fetus as modified by ultrasonic
measurements of fetal long bones.
SUMMARY OF THE INVENTION
The
present invention pertains to a method for the prenatal detection of trisomy 21
in the second trimester by adjusting the risk of trisomy 21 based on fetal long
bone biometry which comprises the steps of:
(a) measuring ultrasonically
the biparietal diameter and the length of the femur, humerus, tibia, and fibula
bones in fetuses of a patient population in the second trimester;
(b)
performing amniocentesis on the patient population in step (a) to determine
which fetuses are normal and which fetuses have trisomy 21;
(c) from the
normal fetuses, deriving equations describing the predicted lengths of the
femur, humerus, tibia, and fibula based on the biparietal diameter measurements;
(d) calculating a ratio of observed lengths to predicted lengths of the
femur, humerus, tibia, and fibula for all fetuses;
(e) comparing the
ratios calculated in step (d) for normal fetuses against the ratios calculated
for fetuses having trisomy 21 and determining a threshold, as a percentile of
these ratios, for abnormally short bone lengths in the fetuses having trisomy
21; and
(f) employing the threshold determined in step (e) to detect
prenatally trisomy 21 by fetal long bone biometry.
The present invention
also pertains to a method for the prenatal detection of trisomy 21 in the second
trimester by adjusting the risk of trisomy 21 based on fetal long bone biometry
which comprises the steps of:
(a) measuring ultrasonically the
biparietal diameter and the length of the femur, humerus, tibia, and fibula
bones in fetuses of a patient population in the second trimester;
(b)
performing amniocentesis on the patient population in step (a) to determine
which fetuses are normal and which fetuses have trisomy 21;
(c) from the
normal fetuses, deriving equations describing the predicted lengths of the
femur, humerus, tibia, and fibula based on the biparietal diameter measurements;
(d) calculating a ratio of observed lengths to predicted lengths of the
femur, humerus, tibia, and fibula for all fetuses;
(e) comparing the
ratios calculated in step (d) for normal fetuses against the ratios calculated
for fetuses having trisomy 21 and determining a threshold, as a percentile of
these ratios, for abnormally short bone lengths in the fetuses having trisomy
21;
(f) employing the threshold determined in step (e) to determine
sensitivity and specificity in detecting prenatally trisomy 21 by fetal long
bone biometry; and
(g) employing the sensitivity and specificity
determined in step (f) to adjust the risk of trisomy 21.
DETAILED
DESCRIPTION OF THE INVENTION
In accord with the present invention,
applicants have established the efficacy of long bone biometry, including
measurements of femur, humerus, tibia and fibula, in detecting trisomy 21 in the
second trimester of pregnancy by adjusting the risk of trisomy 21 and have
generated tables that allow adjusting the risk for trisomy 21, and therefore the
need for genetic amniocentesis, depending on fetal long bone biometry. Four long
bones, femur, humerus, tibia and fibula, were ultrasonically measured in
singleton fetuses prior to genetic amniocentesis. Fetuses with normal karyotypes
were used to derive regression equations describing predicted femur, humerus,
tibia and fibula on the basis of the biparietal diameter (BPD) measurement.
Observed to expected long bone ratios were calculated for each fetus and short
bones were defined as less than the tenth percentiles of these ratios. The
efficacy of each abnormally short bone alone, and in combination, was determined
in 22 fetuses with trisomy 21 encountered during the study period. After the
sensitivity and specificity of long bone biometry was established, appropriate
tables were generated by Bayes' theorem to adjust the risk for trisomy 21 in the
second trimester depending on long bone biometry. Outcome information included
the results of fetal karyotypes obtained by genetic amniocentesis.
A
total of 515 patients between 14 and 23 weeks gestation were included in the
study. Of these, 493 had normal fetal karyotype and 22 had trisomy 21. The
thresholds in terms of observed to expected ratios used to define an abnormally
short bone were: femur length <0.88, humerus length <0.89, tibia length
<0.86, and fibula length <0.86. Using these thresholds, the sensitivity,
specificity, positive and negative predictive values of the femur were 22.7%,
89.9%, 9%, 96.3%; humerus 45.5%, 90%, 17%, 97.4%, tibia 27.3%, 91.3%, 12.2%,
96.6%; and fibula 18.2%, 91%, 8.3%, 96.2%, respectively. The sensitivity of an
abnormal ultrasound, as defined by the presence of one or more short bones, was
63.6%, the specificity 78.5%, the positive predictive value 11.7%, and the
negative predictive value 98%. The sensitivity and specificity of long bone
biometry was independent of maternal age. According to Bayes' theorem, genetic
amniocentesis may not be recommended for women under 40 years old in the
presence of normal long bone biometry (all four bones normal). In summary,
second trimester fetal long bone biometry is useful in detecting trisomy 21 and
may be used to adjust the a priori risk of both high and low risk women for
trisomy 21 and therefore the need for genetic amniocentesis.
Results
The study consisted of 515 fetuses, 493 were karyotypically normal and
22 had trisomy 21. The maternal age was 34.8.+-.4.9 (mean.+-.SD) years and the
gestational age at the time of amniocentesis was 17.3.+-.1.6 (mean+SD) weeks.
Indications for genetic amniocentesis included advanced maternal age (65%),
abnormal serum screening (26%), and other indications (9%). The regression
equations for determining the expected (predicted) value of each bone
measurement according to the measured BPD are shown in Table I. The abnormal
observed to expected ratios (thresholds) were as follows: short femur<0.88,
short humerus<0.89, short tibia<0.86, and short fibula<0.86. Table II
shows the specific thresholds for a wide range of BPD measurements. Using these
thresholds, the sensitivity, specificity, positive and negative predictive
values of each bone alone, and in combination, in detecting trisomy 21 were
calculated (Table III). Table IV describes in detail the long bone findings in
trisomy 21 fetuses. Since application of the Bayes' theorem requires conditional
independence (i.e., maternal age independence) the next step was to determine if
the sensitivity and specificity varied according to maternal age. Table V shows
that there were no differences in the sensitivity or specificity of long bone
biometry between women under 36 versus women 36 years old or older. Using the
sensitivities and specificities established in Table III, Bayes' theorem was
applied to generate risk estimates for trisomy 21 on the basis of fetal long
bone biometry combined with either maternal age (Table V1) or serum biochemical
screening (Table VII). As shown, of the individual bones, a short humerus had
the highest sensitivity (45.5%), whereas the sensitivity of using "one or more
abnormally short bones" as the abnormal test was 63.6%, with a specificity of
78.5%
Discussion
Prenatal diagnosis of trisomy 21 in the second
trimester of pregnancy has traditionally relied on amniocentesis in women 35
years of age or older. Using maternal age as a screening method, however, will
identify only 20% of trisomy 21 cases with a false positive rate of
approximately 5-7%. It is generally accepted that the average pregnancy loss
associated with genetic amniocentesis is approximately 1 in 270. When advanced
maternal age alone is used to screen for trisomy 21, approximately 140
amniocenteses are required to discover one fetus with trisomy 21.sup.17. This
implies that one normal fetus may be lost for every two fetuses identified with
trisomy 21. In recent years, the combination of maternal age and serum
biochemical screening (maternal serum alpha-fetoprotein, estriol, human
chorionic gonadotropin) has been shown to identify approximately 60-65% of
fetuses with trisomy 21.sup.20. This approach has false positive rates ranging
from 5-10% but still does not focus on the right group of candidates for
amniocentesis because approximately 60-70 amniocenteses are needed to detect one
fetus with trisomy 21.sup.17. Thus, even with the most current screening
techniques, one normal fetus may be lost as a complication of genetic
amniocentesis for every three to four fetuses identified with trisomy 21. It is
therefore desirable to develop techniques to optimize selection of candidates
for invasive prenatal testing in order to decrease procedure-related losses of
normal fetuses without significantly reducing detection rates.
In one
study, the English literature was reviewed and established the overall
sensitivity and specificity of sonographic markers of fetal aneuploidy in order
to generate tables for adjusting the risk for trisomy 21.sup.17. According to
that review, high sensitivities (83-91%) for detecting trisomy 21 were reported
by experienced investigators.sup.17. Therefore, the prerequisite for such an
ultrasound examination is skill and experience in diagnosing fetal structural
malformations and especially congenital heart disease. Such an expertise,
however, is not widely available. As a result, ultrasound adjustment of the risk
for trisomy 21 has not been incorporated into general practice. The purpose of
this study was to report a simple method for adjusting trisomy 21 risk using
four fetal bones i.e., femur, humerus, tibia, and fibula. The advantage of this
approach is that great expertise usually is not required for identifying and
measuring a long bone. However, the accuracy of these measurements and the
applicability of the ratios may vary between different ultrasound units or
different populations. Therefore, each institution should establish their
patient thresholds for defining "shortness" of a particular bone.
The
present study established thresholds for defining "shortness" for femur,
humerus, tibia, and fibula in our own patient population. Using these
thresholds, when one or more of these bones are abnormally short, the risk for
trisomy 21 is increased. On the other hand, a normal long bone biometry (all
four bones normal) theoretically decreases the a priori risk for trisomy 21 by
approximately 63%. Adjusting the risk for trisomy 21 based upon fetal long bone
biometry is a simple method which may lead to increased or decreased risk for
individual patients. For instance, many low risk women who have an ultrasound
for other indications may be found to have short one or more fetal bones and
therefore at increased risk for trisomy 21. On the other hand, if the currently
accepted risk (1:274) of a 35 year old woman is used as an indication for
offering genetic amniocentesis, genetic amniocentesis may not be considered in
the presence of normal long bone biometry except in women 40 years old or older.
This ultrasound risk adjustment may lead to better selection of candidates for
amniocentesis with higher yields of positive amniocentesis results, thus
minimizing the procedure-related losses of normal fetuses. As shown in Table IV,
a short fibula did not add to the overall detection rate. However, a larger
number of fetuses with trisomy 21 need to be accumluated before a final decision
can be made that fibula measurements should be omitted. Consequently, fibula was
kept as one of the four bones to be measured to adjust risks.
The
adjusted risks in Tables VI and VII assume the absence of gross fetal structural
malformations, although in our 22 trisomy 21 cases two were found to have small
ventricular septal defects and one had abnormal nuchal fold thickening during
the basic scanning performed prior to amniocentesis. It should be emphasized
that the risks illustrated in Tables VI and VII are based in mathematic modeling
and, therefore, are purely theoretical and may change appreciably once large
prospective studies become available. Patients should be counseled that with
this approach, some cases with trisomy 21 may be missed.
The routine use
of these tables on every patient who has second trimester ultrasonography should
neither increase nor decrease the total number of amniocenteses. The impact of
ultrasound adjusted risk for trisomy 21 in the general population is illustrated
in FIG. 1. In deriving the algorithm of FIG. 1, the following assumptions were
made: I) Approximately 5% of the pregnant population are women 35 years old or
older; of these, approximately 80% are between the ages 35-39; and approximately
20% are 40 years old or older. Women who are 40 years old or older regardless of
the ultrasound results, even with normal long bone biometry, have a risk for
trisomy 21 greater than or equal to 1:274 and therefore should be offered
amniocentesis. However, approximately 80% of the advanced maternal age
population are women between the ages 35-39. Of these women, 80% would have a
normal ultrasound with an adjusted risk of less than 1:274 and, therefore, would
not be candidates for amniocentesis. The remaining 20% would have abnormal
ultrasound and therefore, should be offered amniocentesis period. 2)
Approximately 3% of the population are women under 35 years old who are at
increased risk for trisomy 21 based upon abnormal serum screening. Of these
women, 20% would have abnormal ultrasound and should be lo offered
amniocentesis, whereas the remaining 80% would have a normal ultrasound. In
approximately half of the patients with normal ultrasound, the risk may still be
greater than or equal to 1:274 and therefore amniocentesis may be offered;
whereas in the remaining 50% the risk may become less than 1:274 and
amniocentesis may not be needed; 3) The third group of women that an
ultrasound-adjusted risk for trisomy 21 may be indicated for is the low risk
population of women younger than 35 years of age. Approximately 70% of these
women may have a second trimester sonogram for some other indication.
Approximately 80% will have a normal ultrasound and therefore amniocentesis is
not medically indicated. The remaining 20% will have an abnormal ultrasound. In
approximately 70% of these cases, the risk may still be less than 1:274 and
amniocentesis may not be indicated, whereas in the remaining 30% the risk may
become greater than or equal to 1:274 and an amniocentesis may be offered. If
the above assumptions are correct, the total amniocentesis rate generated by
routinely incorporating the ultrasound-adjusted risk for trisomy 21 on every
patient who has ultrasonography is 76/1,000 or 7.6%. This rate is not different
from the rate of 80/1,000 (or 8%) generated by the current practice of offering
routinely amniocentesis to women 35 years old or older and to all younger women
with abnormal serum screening. The end result, however, may be better selection
of candidates for an invasive procedure with known complications.
The
most compelling argument for the use of individualized ultrasound-adjusted risks
is respect for maternal autonomy. Since the risk of having a child with trisomy
21 may not have the same significance compared to the risk of losing a normal
fetus (as a result of genetic amniocentesis) for all patients, individualization
of the degree of risks should be part of the informed consent. It is the
physician's duty to provide all necessary information to the patient and proceed
with an invasive genetic procedure only if the couple agrees. It should not be
the physician's position to recommend for or against amniocentesis. This is an
individual decision which should be made by the patient and not the physician.
Ultrasonography by simple fetal bone biometry may help in individualizing the
informed consent process of these patients.
The present invention is
further illustrated by the following examples which are not intended to limit
the effective scope of the claims. All parts and percentages in the examples and
throughout the specification and claims are by weight of the final composition
unless otherwise specified.
Source: http://www.uspto.gov/patft/ | |
Revised: February 14, 2001. |