Single Versus Multiple Echogenic Foci in the Fetal Heart

1. Comparison of Single Versus Multiple
Echogenic Foci in the Fetal Heart
Regarding Risk of Aneuploidy
Dena Towner, MD, Eugenio O. Gerscovich, MD,
Brian B. Chiong, MD, Laila Rhee-Morris, MS,
John P. McGahan, MD
Objective.The purpose of this study was to investigate whether multiple echogenic cardiac foci (ECF)
are associated with an increased risk of fetal trisomy 21 in our patient population. Methods.During a
span of 38 months, all women found to have an ECF on obstetric sonography were identified as study
patients and grouped into single- and multiple-ECF groups. Age- and race-matched patients were
identified as a control group. Fetal anatomic sonographic examinations were assessed for other mark-
ers of aneuploidy and major abnormalities. The baseline risk for trisomy 21 was assessed by maternal
serum screening or age alone if no serum screening had been performed. Trisomy 21 was assessed by
amniocentesis or clinically at birth. Both univariate and multivariate analyses were used to assess for
associations with trisomy 21. Results.Six of 71 patients (8.5%) with multiple ECF and 1 of 171
patients (0.6%) with a single ECF had trisomy 21. One of 242 control patients (0.4%) had trisomy 21.
Logistic regression found multiple ECF (P< .008), the presence of a major finding or multiple minor find-
ings (P = .0012), and a baseline risk for trisomy 21 of greater than 1 in 100 (P= .003) as independent
associations with trisomy 21. Conclusions.Our results suggest that finding multiple ECF is a stronger
predictor of trisomy 21 than what is described for a single ECF.Key words: echogenic cardiac focus;
fetal aneuploidy; fetal heart; prenatal diagnosis; sonography.
Received November 2, 2009, from the Departments
of Obstetrics and Gynecology (D.T., L.R.-M.), and
Radiology (E.O.G., J.P.M.), University of California,
Davis Health System, Sacramento, California USA;
State University of New York, Downstate Medical
Center, Brooklyn, New York USA (B.B.C.). Revision
requested November 23, 2009. Revised manuscript
accepted for publication March 2, 2010.
We thank John Brock for coordinating Institutional
Review Board approval and organizing data, Steve
Wilkendorf for helping gather data, and Angela
Michelier for invaluable administrative assistance
and timely processing of the manuscript.
Address correspondence to Eugenio O.
Gerscovich, MD, Department of Radiology, University
of California, Davis Health System, 4860 Y St, Suite
3100, Sacramento, CA 95817 USA.
E-mail address: eugenio.gerscovich@ucdmc.
ucdavis.edu
Abbreviations ECF, echogenic cardiac focus he presence of an echogenic cardiac focus (ECF)
within the fetal heart is relatively common. When
it was first described in 1986, an ECF was origi-
nally thought to be a benign finding.
1
In 1994, an
ECF was correlated pathologically with mineralization
within the papillary muscle.
2
More recently, a number of
studies have suggested an association between the pres-
ence of an ECF and an increased risk of fetal aneuploidy,
specifically trisomies 21, 13, and 18.
3–7
The exact clinical
importance of this relationship in terms of counseling
patients has been controversial. Studies by Bradley et al
8
and Ouzounian et al
9
suggested that the presence of an
ECF without other risk factors for aneuploidy (eg,
advanced maternal age and abnormal serum triple-
marker screening results) may not warrant amniocente-
sis because the predictive value of an isolated ECF in their
analyses appeared to be low. However, it appears that the
risk of multiple ECF has not yet been well explored
because we were able to find only 2 mentions of multiple
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2. ECF in the literature,
10,11
both of which had iden-
tified few cases of multiple ECF (6 in 1 study and
9 in the other) and with opposite conclusions as
to their importance. The purpose of this study
was to elucidate the risk for trisomy 21 with mul-
tiple ECF.
Materials and Methods
This retrospective case cohort study was
approved by our Institutional Review Board and
complied with all of its standards. Over a 38-
month period (September 1, 2004–November 1,
2007) patients who received fetal anatomic
sonographic examinations at our institution
were eligible for this study. The indications for
sonography included a routine anatomic survey,
abnormal maternal serum screening results,
advanced maternal age (≥35 years at delivery),
medication or teratogen exposure, an abnormal-
ity suggested on prior sonography, and a family
history possibly affecting the fetus.
The study cases were identified by 2 methods to
ensure capturing all cases during the study time
frame. First, every time that an ECF was identi-
fied in a sonographic examination, the patient
demographics were entered by the sonographer
or radiologist onto a list kept by one of the
authors (E.O.G.). Second, a query was run from
the prenatal database (Microsoft Access;
Microsoft Corporation, Redmond, WA), where all
findings were entered at the time of the sono-
graphic examinations and reviewed by one of the
authors (D.T.). Control cases were obtained by
identifying the next maternal age- and race-
matched patient seen in the same prenatal diag-
nostic clinic. Gestational age matching was not
feasible. The fetuses with ECF were categorized
into a single focus (ECF-1) and multiple foci
(ECF-2). Although many of these patients had
several examinations, each patient was only
counted once in the study. Data collected on
each patient included maternal age at the esti-
mated date of delivery, race, other sonographic
findings, risk assessment for trisomy 21 based on
maternal serum screening or age, and assess-
ment for trisomy 21 on the fetus or neonate by
karyotype or neonatal examination. Serum
screening risk assessment was preferentially
used for all patients when available. Age risk
assessment was only used for those patients who
did not have serum screening. Risk assessment
for trisomy 21 was categorized into 4 groups: very
low risk, less than 1 in 1000; low risk, 1 in 500 to 1
in 1000; intermediate risk, 1 in 100 to 1 in 500;
and high risk, greater than 1 in 100.
All sonographic examinations were performed
with Acuson Sequoia scanners (Siemens Medical
Solutions, Mountain View, CA) using vector and
curved transducers with a frequency of 4 to 8
MHz. These examinations were then interpreted
by either a board-certified radiologist or a peri-
natologist with expertise in prenatal sonography.
Sonographic examinations included a detailed
fetal anatomic survey as per the American
Institute of Ultrasound in Medicine guidelines.
12
The determination of a single ECF versus multi-
ple ECF was made during the real-time scan,
documented and confirmed in the written sono-
graphic report, and further confirmed during ret-
rospective image review. A 4-chamber view of the
fetal heart was obtained in all patients; the right
and left ventricular outflow tracts were docu-
mented when possible. The identification of an
ECF in the fetal heart was made when visible in
the papillary muscles in either ventricle. The
examinations were subsequently reviewed by two
of the authors (E.O.G. and B.B.C.) to confirm the
original diagnosis of single or multiple ECF. The
ECF was considered “bright” if it was as echogenic
as or greater than bone, meaning that as the gain
was turned down, the ECF went away at the same
time or after bone. The ECF was considered “mod-
erate” if it was echogenic but as the gain was
turned down, the echogenicity of the ECF was still
present as bone started to go away, but the ECF
went away before the entire bone. Thus, with the
moderate ECF, there was overlapping echogenici-
ty with bone but not as bright or brighter (Figures
1–4). The sonographic reports were reviewed for
other findings associated with an increased risk of
trisomies 21 and 18. Nuchal thickness (via an axial
view) was recorded and considered abnormal if 6
mm or greater during the second-trimester scan.
Femur and humerus lengths were compared to
menstrual dating by the last menstrual period
and to other biometric parameters. We consid-
ered a long bone length of greater than 7 days less
than expected to be a marker. Renal pelviectasis
was defined as a renal pelvis measurement of
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Single Versus Multiple Echogenic Foci in the Fetal Heart
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3. greater than 4 mm in the anteroposterior diam-
eter during the second-trimester scan. Other
biometric measurements, bowel echogenicity,
and other soft or hard markers were noted and
recorded. The presence of just 1 additional
sonographic abnormality was assessed to see
whether that independently increased the risk
of trisomy 21. A “major finding” was considered
the presence of a structural anomaly, nuchal
thickness of greater than 6 mm, or 2 additional
marker abnormalities. A major finding was
assessed as an independent risk factor.
Genetic counseling was provided to patients
with an ECF or another sonographic finding
associated with increased risk of aneuploidy.
Patients were then offered fetal karyotyping by
amniocentesis if desired. Outcomes of these cases
were determined by either amniocentesis or diag-
nosis on delivery or termination. Univariate statis-
tical analysis with a 2-tailed Fisher exact test, a χ
2
test, and analysis of variance was used to identi-
fy differences among the 3 groups. Logistic
regression was then used to identify significant
independent associations with trisomy 21.
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Towner et al
Figure 1. Healthy fetus: 4-chamber view of the heart with 2
bright ECF (arrows), 1 in each ventricle.
Figure 2. Healthy fetus: left ventricular outflow tract (LVOT) view
of the heart with 2 moderate ECF (arrows) in the left ventricle.
Figure 3. Patient 2 (see Table 3), fetus with trisomy 21 at an
estimated gestational age of 15 weeks 1 day: 4-chamber view
of the heart with a moderate ECF (arrow) in the left ventricle.
Figure 4. Patient 5 (see Table 3), fetus with trisomy 21: 4-cham-
ber view of heart with 3 bright ECF (arrow) in the left ventricle.
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4. Results
We found 242 patients with ECF. One hundred
seventy-one patients (70.7%) had ECF-1, and 71
patients (29.3%) had ECF-2. Characteristics of the
3 groups are presented in Table 1. There were 8
fetuses with trisomy 21; 4 were ascertained by
amniocentesis and 4 by newborn examination
and the postnatal karyotype. In these 8 pregnan-
cies, the range of maternal ages was 16 to 44 years.
Gestational ages at the time of detection ranged
from 15 weeks 0 day through 32 weeks 2 days.
The group of women with ECF-2 had the lowest
average risk for having a fetus with trisomy 21
and fewer diagnostic amniocenteses (Table 1).
However, 8.5% of the fetuses in that group had
trisomy 21. Five of the 6 fetuses with trisomy 21
in that group had a baseline risk of having tri-
somy 21 of greater than 1 in 100. The remaining
fetus with trisomy 21 in that group had a risk of 1
in 280, which was 4-fold higher than that expect-
ed for a woman 22 years old. In the subgroup of 8
fetuses with ECF-2 and a trisomy 21 risk of
greater than 1 in 10, 5 (62.5%) had trisomy 21.
Similarly, in the subgroup of fetuses with ECF-1
and a trisomy 21 risk of greater than 1 in 10, only
1 of 36 fetuses (2.7%) had trisomy 21. In the entire
group of fetuses with ECF-1, there was 1 fetus
with trisomy 21 (0.6%) and 1 fetus with trisomy
21 (0.4%) in the control group, which was in
sharp contrast to the 8.5% in the ECF-2 group.
We addressed whether there was any difference
in bright and moderate echogenicity and an
association with trisomy 21. There was a trend
toward significance for both, with a moderate
focus having a value of P= .22 on the Fisher
exact test and a bright focus having a value of
P= .38. In a logistic regression model with tri-
somy risk and other sonographic findings (both
markers and major), both bright (P= .085) and
moderate (P= .088) foci were nearly associated
with trisomy 21. Thus, in our laboratory, these
two descriptions for an ECF were equal in
meaning.
Using logistic regression, we found that ECF-2
by itself had a strong association with trisomy 21
independent of the baseline risk of trisomy
21 (Table 2). A baseline risk of trisomy 21 of
greater than 1 in 100 or a major finding (>1 addi-
tional marker, nuchal fold >6 mm, or a major
malformation) was also highly associated with
trisomy 21.
We looked at specific findings in the 7 cases of
trisomy 21 with ECF (Table 3). The ECF was
bright in 2 cases and moderate in 5, which was
not statistically significant. In only 4 of the 8
cases with trisomy 21 were there additional
sonographic abnormalities. In the 1 case with-
out an ECF, there was a major heart defect iden-
tified in a 16-year-old patient who presented too
late for serum screening. In the case with nega-
tive maternal serum screening results (but 4-fold
Single Versus Multiple Echogenic Foci in the Fetal Heart
Table 1.Characteristics of the Study Groups
Characteristic ECF-2 ECF-1 No ECF P
Cases, n 71 171 242
Age, y, mean ± SD 27.8 ± 6.6 30.8 ± 7.5 30.0 ± 7.1 .016
Indication for prenatal diagnosis, n (%) <.0001
Advanced maternal age 9 (13) 50 (29) 67 (28)
Abnormal sonographic findings 23 (32) 70 (41) 25 (10)
Family history or medication exposure 28 (39) 25 (15) 76 (31)
Abnormal serum screening 11 (15) 26 (15) 74(31)
Race, n (%) .82
White 31 (44) 68 (40) 101 (42)
African American 15 (21) 37 (22) 53 (22)
Hispanic 8 (11) 33 (19) 41 (17)
Asian 16 (23) 29 (16) 46 (19)
Amniocentesis, n (%) 17 (24) 54 (32) 89 (36) .12
Average risk of trisomy 21 1/3831 1/2322 1/1809 <.0001
Additional marker, n (%) 9 (13) 14 (8) 8 (3) .0089
Major finding, n (%) 4 (2.6) 4 (2) 14 (5.7) .22
Trisomy 21, n (%) 6 (8.5) 1 (0.6) 1 (0.4) <.0001
Bright ECF, n (%) 27 (38) 82 (48) 0
Moderate ECF, n (%) 44 (61) 89 (52) 0
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Towner et al
greater than her age-related risk), the fetus was
noted to have a prominent umbilical vein and
ambiguous genitalia, which are not findings typ-
ically associated with trisomy 21.
Discussion
The utility of an ECF as a marker for fetal aneu-
ploidy has been controversial because it is one of
the so-called soft markers that seem to indicate a
relatively low predictive value as an isolated find-
ing.
8,9
Although soft markers such as increased
nuchal thickness of 6 mm or greater have been
shown to have high sensitivity for detection of
trisomy 21 in almost all studies, the same cannot
be said for an ECF. Part of the controversy lies in
what corresponds to an ECF compared to a mea-
surement of nuchal thickness. Nuchal thickness
is a precise measurement obtained on a defined
anatomic plane that is highly reproducible.
Alternatively, an ECF is less precise, with variables
including definition of an ECF (foci brighter than
bone), fetal position (apex up), maternal body
habitus, and even race. Controversy is further
compounded by single versus multiple ECF.
Limited studies have shown opposing conclu-
sions regarding the importance of multiple ECF.
This becomes the basis of the current study. We
found that multiple ECF are highly associated
with an increased risk for trisomy 21, indepen-
dent of the baseline risk and other sonographic
findings. Overall, there was an 8.5% chance of tri-
somy 21 if ECF-2 was found; however 5, of these
6 cases of trisomy 21 were in women at high risk
based on the baseline risk assessed either by age
alone or on serum screening. Thus, similar to a
single ECF, one must put the finding in the con-
text of the entire situation, including the baseline
risk and other sonographic findings.
The strength of this study was that for each
patient, her individual baseline risk for trisomy
21 was incorporated into the assessment. In
addition, other sonographic findings were inde-
pendently assessed. We also matched for race
because ECF have been noted to have different
prevalence rates in different racial groups.
Table 2. Associations With Trisomy 21 on Logistic Regression
Parameter Odds Ratio Confidence Interval
ECF-1 1.2 0.05–31
ECF-2 50 2.7–927
Intermediate risk for trisomy 21 5.2 0.18–152
High risk for trisomy 21 82 4.7–1438
1 additional marker 2.7 0.022–34
Major finding 44 4.4–440
Table 3. Data on Patients With Trisomy 21
ECF Maternal Gestational Trisomy 21 Risk Other Sonographic
Patient Characteristics
a
Age, y
b
Age, wk + d
c
Risk Calculation Abnormalities Race
No ECF
1 0 16 32 + 2 1/1572 Age TOF, absent NB Hispanic
ECF-1
2 1 moderate, left ventricle 40 15 + 1 1/91 Age None White
ECF-2
3 2 moderate, left ventricle 22 23 + 2 1/280 Serum Ambiguous genitalia, White
lack of umbilical coiling,
prominent umbilical vein
(7 mm)
4 2 moderate, left ventricle 34 20 + 2 >1/10 Serum Renal pelvis (4.6 and Hispanic
5.6 mm)
5 3 bright, left ventricle 30 20 + 3 1/91 Serum None Asian
6 2 bright, left ventricle, 38 18 + 6 1/56 Serum None White
and increased echogenicity
at apex
7 2 moderate, left ventricle 20 19 + 6 1/91 Serum None White
8 2 moderate, left ventricle 44 15 + 0 1/28 Age None (short limbs) White
NB indicates nasal bone; and TOF, tetralogy of Fallot.
a
Number of ECF, degree of echogenicity, and location.
b
At the estimated due date.
c
At the time of findings.
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6. A weakness of the study was that we used a
predominantly prenatal diagnosis population
in which the baseline risk for trisomy 21 was
increased over the general obstetric population;
thus, the risk for aneuploidy may be less in other
settings. However, multiple ECF should still serve
as a finding on a routine obstetric study that
would warrant referral for prenatal diagnosis.
The indications for prenatal diagnosis were dif-
ferent between the groups, and this was primari-
ly related to the fact that a large percentage of the
ECF groups were referred for that indication
from outside providers. Because the baseline risk
for trisomy 21 and sonographic findings are the
two main correlations with a fetus having tri-
somy 21, the reason for referral should not have
an independent association with trisomy 21.
We recognize the limitations of this study,
including the small population studied as well as
potential interobserver variability inherent in
diagnosing ECF on sonography. We tried to cor-
rect for this variability by independently review-
ing each of the cases presented in this study to
standardize criteria by which to determine the
existence of ECF. Regarding technical factors, we
are well aware that thin, small patients allow for
the use of higher-frequency transducers, which
will increase the detection of ECF. A cardiac-
apex-up fetal position will do the same. We tried
to avoid these pitfalls.
The single case of trisomy 21 with ECF-1 was
our earliest detection at 15 weeks 1 day and had
a single ECF of moderate intensity (Figure 3). Of
the ECF-2-associated fetuses with trisomy 21,
there were 2 cases that showed bright ECF and 4
cases showing moderate ECF (Figure 4). In
reviewing the past literature detailing the nature
of ECF, definitions often include that the ECF
should match the intensity of fetal bone.
Echogenicity is a continuum and dependent on
the transducer frequency, depth, and angle of
insonation. Thus, it is hard to place echogenic
appearance in discrete categories. We chose to
separate out a group in which the ECF was not as
bright or brighter but did overlap with the
echogenicity of bone. Had we used the strictest
definition, we could have missed more than half
of the cases of trisomy 21 identified.
Although our study yielded 32 cases of ECF
occurring in the right ventricle, most of our cases
identified ECF in the left ventricle only, and each
of our cases of trisomy 21 showed ECF in the left
ventricle only. This differs from a previous study
suggesting that right ventricular ECF were more
indicative of trisomy 21 when compared to left-
sided ECF only.
10
Despite the fact that the population for this
study was relatively small, it was nevertheless
notable that 8.5% of the cases we identified with
multiple ECF did in fact end up with trisomy 21
compared to 0.6% of our patients with a single
ECF and 0.4% in the control group. Prior studies
revealed likelihood ratios of various soft markers
for trisomy 21. The marker with the highest sen-
sitivity for detection of trisomy 21 is nuchal
thickness, using a value of 6 mm or greater.
Benacerraf et al
13
found sensitivity of 43% and a
false- positive rate of 0.1%. Others, such as Smith-
Bindman et al,
14
showed a likelihood ratio of 17
using meta-analysis. However, there has been
less enthusiasm for the use of an ECF as a major
soft marker for trisomy 21. Likelihood ratios have
been reported ranging from 1.4 to 2.8.
15
Maternal
weight may prove to be an important factor in
detecting an ECF in the fetal heart. An ECF in the
fetal heart of a thin woman may have little
importance. Race has also been shown to affect
the importance of the finding.
16
In most series, the usual recommendation
when finding a second-trimester fetal ECF is to
correlate it with biochemical markers, maternal
age, and level II obstetric sonography. Our results
suggest that a finding of multiple ECF is a
stronger predictor of trisomy 21 than described
for a single ECF. However, the finding needs to be
put in the context of the situation, and if a patient
has both a high risk for trisomy 21 and multiple
ECF, the fetus may have well greater than a 50%
chance of having trisomy 21.
References
1. Allan LD. Manual of Fetal Echocardiography. London,
England: MTP Press; 1986:134.
2. Brown DL, Roberts DJ, Miller WA. Left ventricular
echogenic focus in the fetal heart: pathologic correlation.
J Ultrasound Med 1994; 13:613–616.
1066 J Ultrasound Med 2010; 29:1061–1067
Single Versus Multiple Echogenic Foci in the Fetal Heart
297online.qxp:Layout 1 6/21/10 2:42 PM Page 1066

7. 3. Bromley B, Lieberman E, Shipp TD, Richardson M,
Benacerraf BR. Significance of an echogenic intracardiac
focus in fetuses at high and low risk for aneuploidy. J
Ultrasound Med 1998; 17:127–131.
4. Vibhakar NI, Budorick NE, Scioscia AL, Harby LD, Mullen
ML, Sklansky MS. Prevalence of aneuploidy with a cardiac
intraventricular echogenic focus in an at-risk patient popu-
lation. J Ultrasound Med 1999; 18:265–268.
5. Wax JR, Philput C. Fetal intracardiac echogenic foci: does it
matter which ventricle? J Ultrasound Med 1998; 17:145–
146.
6. Winter TC, Anderson AM, Cheng EY, et al. Echogenic
intracardiac focus in 2nd-trimester fetuses with trisomy 21:
usefulness as a US marker. Radiology 2000; 216:450–456.
7. Manning JE, Ragavendra N, Sayre J, et al. Significance of
fetal intracardiac echogenic foci in relation to trisomy 21: a
prospective sonographic study of high-risk pregnant
women. AJR Am J Roentgenol 1998; 170:1083–1084.
8. Bradley KE, Santulli TS, Gregory KD, Herbert W, Carlson
DE, Platt LD. An isolated intracardiac echogenic focus as a
marker for aneuploidy. Am J Obstet Gynecol 2005;
192:2021–2028.
9. Ouzounian JG, Ludington C, Chan S. Isolated choroid
plexus cyst or echogenic cardiac focus on prenatal ultra-
sound: is genetic amniocentesis indicated? Am J Obstet
Gynecol 2007; 196:595.e1–e3.
10. Bronshtein M, Jakobi P, Ofir C. Multiple fetal intracardiac
echogenic foci: not always a benign sonographic finding.
Prenat Diagn 1996; 16:131–135.
11. Petrikovsky B, Challenger M, Gross B. Unusual appear-
ances of echogenic foci within the fetal heart: are they
benign? Ultrasound Obstet Gynecol 1996; 8:229–231.
12. American Institute of Ultrasound in Medicine. AIUM prac-
tice guideline for the performance of an antepartum
obstetric ultrasound examination. J Ultrasound Med 2003;
22:1116–1125.
13. Benacerraf BR, Frigoletto FD Jr, Cramer DW. Down syn-
drome: sonographic sign for diagnosis in the second-
trimester fetus. Radiology 1987; 163:811–813.
14. Smith-Bindman R, Hosmer W, Feldstein VA, Deeks JJ,
Goldberg JD. Second-trimester ultrasound to detect fetus-
es with Down syndrome: a meta-analysis. JAMA 2001;
285:1044–1055.
15. Bromley B, Lieberman E, Shipp TD, Benacerraf BR. The
genetic sonogram: a method of risk assessment for Down
syndrome in the second trimester. J Ultrasound Med 2002;
21:1087–1096.
16. Borgida AF, Maffeo C, Gianferarri EA, Bolnick AD, Zelop
CM, Egan JF. Frequency of echogenic intracardiac focus by
race/ethnicity in euploid fetuses. J Matern Fetal Neonatal
Med 2005; 18:65–66.
J Ultrasound Med 2010; 29:1061–1067 1067
Towner et al
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