Single Versus Multiple Echogenic Foci in the Fetal Heart

Article 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 markers 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 findings (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. T Abbreviations he presence of an echogenic cardiac focus (ECF) ECF, echogenic cardiac focus 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 Received November 2, 2009, from the Departments within the papillary muscle.2 More recently, a number of of Obstetrics and Gynecology (D.T., L.R.-M.), and studies have suggested an association between the pres- Radiology (E.O.G., J.P.M.), University of California, ence of an ECF and an increased risk of fetal aneuploidy, Davis Health System, Sacramento, California USA; State University of New York, Downstate Medical specifically trisomies 21, 13, and 18.3–7 The exact clinical Center, Brooklyn, New York USA (B.B.C.). Revision importance of this relationship in terms of counseling requested November 23, 2009. Revised manuscript accepted for publication March 2, 2010. patients has been controversial. Studies by Bradley et al8 We thank John Brock for coordinating Institutional and Ouzounian et al9 suggested that the presence of an Review Board approval and organizing data, Steve Wilkendorf for helping gather data, and Angela ECF without other risk factors for aneuploidy (eg, Michelier for invaluable administrative assistance advanced maternal age and abnormal serum triple- and timely processing of the manuscript. marker screening results) may not warrant amniocente- Address correspondence to Eugenio O. Gerscovich, MD, Department of Radiology, University sis because the predictive value of an isolated ECF in their of California, Davis Health System, 4860 Y St, Suite analyses appeared to be low. However, it appears that the 3100, Sacramento, CA 95817 USA. E-mail address: eugenio.gerscovich@ucdmc. risk of multiple ECF has not yet been well explored ucdavis.edu because we were able to find only 2 mentions of multiple © 2010 by the American Institute of Ultrasound in Medicine • J Ultrasound Med 2010; 29:1061–1067 • 0278-4297/10/$3.50

Single Versus Multiple Echogenic Foci in the Fetal Heart ECF in the literature,10,11 both of which had iden- assessment was only used for those patients who tified few cases of multiple ECF (6 in 1 study and did not have serum screening. Risk assessment 9 in the other) and with opposite conclusions as for trisomy 21 was categorized into 4 groups: very to their importance. The purpose of this study low risk, less than 1 in 1000; low risk, 1 in 500 to 1 was to elucidate the risk for trisomy 21 with mul- in 1000; intermediate risk, 1 in 100 to 1 in 500; tiple ECF . and high risk, greater than 1 in 100. All sonographic examinations were performed Materials and Methods with Acuson Sequoia scanners (Siemens Medical Solutions, Mountain View, CA) using vector and This retrospective case cohort study was curved transducers with a frequency of 4 to 8 approved by our Institutional Review Board and MHz. These examinations were then interpreted complied with all of its standards. Over a 38- by either a board-certified radiologist or a peri- month period (September 1, 2004–November 1, natologist with expertise in prenatal sonography. 2007) patients who received fetal anatomic Sonographic examinations included a detailed sonographic examinations at our institution fetal anatomic survey as per the American were eligible for this study. The indications for Institute of Ultrasound in Medicine guidelines.12 sonography included a routine anatomic survey, The determination of a single ECF versus multi- abnormal maternal serum screening results, ple ECF was made during the real-time scan, advanced maternal age (≥35 years at delivery), documented and confirmed in the written sono- medication or teratogen exposure, an abnormal- graphic report, and further confirmed during ret- ity suggested on prior sonography, and a family rospective image review. A 4-chamber view of the history possibly affecting the fetus. fetal heart was obtained in all patients; the right The study cases were identified by 2 methods to and left ventricular outflow tracts were docu- ensure capturing all cases during the study time mented when possible. The identification of an frame. First, every time that an ECF was identi- ECF in the fetal heart was made when visible in fied in a sonographic examination, the patient the papillary muscles in either ventricle. The demographics were entered by the sonographer examinations were subsequently reviewed by two or radiologist onto a list kept by one of the of the authors (E.O.G. and B.B.C.) to confirm the authors (E.O.G.). Second, a query was run from original diagnosis of single or multiple ECF The. the prenatal database (Microsoft Access; ECF was considered “bright” if it was as echogenic Microsoft Corporation, Redmond, WA), where all as or greater than bone, meaning that as the gain findings were entered at the time of the sono- was turned down, the ECF went away at the same graphic examinations and reviewed by one of the time or after bone. The ECF was considered “mod- authors (D.T.). Control cases were obtained by erate” if it was echogenic but as the gain was identifying the next maternal age- and race- turned down, the echogenicity of the ECF was still matched patient seen in the same prenatal diag- present as bone started to go away, but the ECF nostic clinic. Gestational age matching was not went away before the entire bone. Thus, with the feasible. The fetuses with ECF were categorized moderate ECF there was overlapping echogenici- , into a single focus (ECF-1) and multiple foci ty with bone but not as bright or brighter (Figures (ECF-2). Although many of these patients had 1–4). The sonographic reports were reviewed for several examinations, each patient was only other findings associated with an increased risk of counted once in the study. Data collected on trisomies 21 and 18. Nuchal thickness (via an axial each patient included maternal age at the esti- view) was recorded and considered abnormal if 6 mated date of delivery, race, other sonographic mm or greater during the second-trimester scan. findings, risk assessment for trisomy 21 based on Femur and humerus lengths were compared to maternal serum screening or age, and assess- menstrual dating by the last menstrual period ment for trisomy 21 on the fetus or neonate by and to other biometric parameters. We consid- karyotype or neonatal examination. Serum ered a long bone length of greater than 7 days less screening risk assessment was preferentially than expected to be a marker. Renal pelviectasis used for all patients when available. Age risk was defined as a renal pelvis measurement of 1062 J Ultrasound Med 2010; 29:1061–1067

Towner et al 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 1. Healthy fetus: 4-chamber view of the heart with 2 bright ECF (arrows), 1 in each ventricle. greater than 4 mm in the anteroposterior diam- Genetic counseling was provided to patients eter during the second-trimester scan. Other with an ECF or another sonographic finding biometric measurements, bowel echogenicity, associated with increased risk of aneuploidy. and other soft or hard markers were noted and Patients were then offered fetal karyotyping by recorded. The presence of just 1 additional amniocentesis if desired. Outcomes of these cases sonographic abnormality was assessed to see were determined by either amniocentesis or diag- whether that independently increased the risk nosis on delivery or termination. Univariate statis- of trisomy 21. A “major finding” was considered tical analysis with a 2-tailed Fisher exact test, a χ2 the presence of a structural anomaly, nuchal test, and analysis of variance was used to identi- thickness of greater than 6 mm, or 2 additional fy differences among the 3 groups. Logistic marker abnormalities. A major finding was regression was then used to identify significant assessed as an independent risk factor. independent associations with trisomy 21. Figure 2. Healthy fetus: left ventricular outflow tract (LVOT) view of the heart with 2 moderate ECF (arrows) in the left ventricle. Figure 4. Patient 5 (see Table 3), fetus with trisomy 21: 4-chamber view of heart with 3 bright ECF (arrow) in the left ventricle. J Ultrasound Med 2010; 29:1061–1067 1063

Single Versus Multiple Echogenic Foci in the Fetal Heart Results We addressed whether there was any difference in bright and moderate echogenicity and an We found 242 patients with ECF One hundred . association with trisomy 21. There was a trend seventy-one patients (70.7%) had ECF-1, and 71 toward significance for both, with a moderate patients (29.3%) had ECF-2. Characteristics of the focus having a value of P = .22 on the Fisher 3 groups are presented in Table 1. There were 8 exact test and a bright focus having a value of fetuses with trisomy 21; 4 were ascertained by P = .38. In a logistic regression model with tri- amniocentesis and 4 by newborn examination somy risk and other sonographic findings (both and the postnatal karyotype. In these 8 pregnan- markers and major), both bright (P = .085) and cies, the range of maternal ages was 16 to 44 years. moderate (P = .088) foci were nearly associated Gestational ages at the time of detection ranged with trisomy 21. Thus, in our laboratory, these from 15 weeks 0 day through 32 weeks 2 days. two descriptions for an ECF were equal in The group of women with ECF-2 had the lowest meaning. average risk for having a fetus with trisomy 21 Using logistic regression, we found that ECF-2 and fewer diagnostic amniocenteses (Table 1). by itself had a strong association with trisomy 21 However, 8.5% of the fetuses in that group had independent of the baseline risk of trisomy trisomy 21. Five of the 6 fetuses with trisomy 21 21 (Table 2). A baseline risk of trisomy 21 of in that group had a baseline risk of having tri- greater than 1 in 100 or a major finding (>1 addi- somy 21 of greater than 1 in 100. The remaining tional marker, nuchal fold >6 mm, or a major fetus with trisomy 21 in that group had a risk of 1 malformation) was also highly associated with in 280, which was 4-fold higher than that expect- trisomy 21. ed for a woman 22 years old. In the subgroup of 8 We looked at specific findings in the 7 cases of fetuses with ECF-2 and a trisomy 21 risk of trisomy 21 with ECF (Table 3). The ECF was greater than 1 in 10, 5 (62.5%) had trisomy 21. bright in 2 cases and moderate in 5, which was Similarly, in the subgroup of fetuses with ECF-1 not statistically significant. In only 4 of the 8 and a trisomy 21 risk of greater than 1 in 10, only cases with trisomy 21 were there additional 1 of 36 fetuses (2.7%) had trisomy 21. In the entire sonographic abnormalities. In the 1 case with- group of fetuses with ECF-1, there was 1 fetus out an ECF, there was a major heart defect iden- with trisomy 21 (0.6%) and 1 fetus with trisomy tified in a 16-year-old patient who presented too 21 (0.4%) in the control group, which was in late for serum screening. In the case with nega- sharp contrast to the 8.5% in the ECF-2 group. tive maternal serum screening results (but 4-fold 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 1064 J Ultrasound Med 2010; 29:1061–1067

Towner et al greater than her age-related risk), the fetus was Table 2. Associations With Trisomy 21 on Logistic Regression noted to have a prominent umbilical vein and Parameter Odds Ratio Confidence Interval ambiguous genitalia, which are not findings typ- ECF-1 1.2 0.05–31 ically associated with trisomy 21. ECF-2 50 2.7–927 Intermediate risk for trisomy 21 5.2 0.18–152 Discussion High risk for trisomy 21 82 4.7–1438 1 additional marker 2.7 0.022–34 Major finding 44 4.4–440 The utility of an ECF as a marker for fetal aneuploidy 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- found that multiple ECF are highly associated ing.8,9 Although soft markers such as increased with an increased risk for trisomy 21, indepen- nuchal thickness of 6 mm or greater have been dent of the baseline risk and other sonographic shown to have high sensitivity for detection of findings. Overall, there was an 8.5% chance of tri- trisomy 21 in almost all studies, the same cannot somy 21 if ECF-2 was found; however 5, of these be said for an ECF Part of the controversy lies in . 6 cases of trisomy 21 were in women at high risk what corresponds to an ECF compared to a mea- based on the baseline risk assessed either by age surement of nuchal thickness. Nuchal thickness alone or on serum screening. Thus, similar to a is a precise measurement obtained on a defined single ECF one must put the finding in the con- , anatomic plane that is highly reproducible. text of the entire situation, including the baseline Alternatively, an ECF is less precise, with variables risk and other sonographic findings. including definition of an ECF (foci brighter than The strength of this study was that for each bone), fetal position (apex up), maternal body patient, her individual baseline risk for trisomy habitus, and even race. Controversy is further 21 was incorporated into the assessment. In compounded by single versus multiple ECF. addition, other sonographic findings were inde- Limited studies have shown opposing conclu- pendently assessed. We also matched for race sions regarding the importance of multiple ECF . because ECF have been noted to have different This becomes the basis of the current study. We prevalence rates in different racial groups. Table 3. Data on Patients With Trisomy 21 ECF Maternal Gestational Trisomy 21 Risk Other Sonographic Patient Characteristicsa Age, yb Age, wk + dc 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. J Ultrasound Med 2010; 29:1061–1067 1065

Single Versus Multiple Echogenic Foci in the Fetal Heart A weakness of the study was that we used a Although our study yielded 32 cases of ECF predominantly prenatal diagnosis population occurring in the right ventricle, most of our cases in which the baseline risk for trisomy 21 was identified ECF in the left ventricle only, and each increased over the general obstetric population; of our cases of trisomy 21 showed ECF in the left thus, the risk for aneuploidy may be less in other ventricle only. This differs from a previous study settings. However, multiple ECF should still serve suggesting that right ventricular ECF were more as a finding on a routine obstetric study that indicative of trisomy 21 when compared to left- would warrant referral for prenatal diagnosis. sided ECF only.10 The indications for prenatal diagnosis were dif- Despite the fact that the population for this ferent between the groups, and this was primari- study was relatively small, it was nevertheless ly related to the fact that a large percentage of the notable that 8.5% of the cases we identified with ECF groups were referred for that indication multiple ECF did in fact end up with trisomy 21 from outside providers. Because the baseline risk compared to 0.6% of our patients with a single for trisomy 21 and sonographic findings are the ECF and 0.4% in the control group. Prior studies two main correlations with a fetus having tri- revealed likelihood ratios of various soft markers somy 21, the reason for referral should not have for trisomy 21. The marker with the highest sen- an independent association with trisomy 21. sitivity for detection of trisomy 21 is nuchal We recognize the limitations of this study, thickness, using a value of 6 mm or greater. including the small population studied as well as Benacerraf et al13 found sensitivity of 43% and a potential interobserver variability inherent in false-positive rate of 0.1%. Others, such as Smith- diagnosing ECF on sonography. We tried to cor- Bindman et al,14 showed a likelihood ratio of 17 rect for this variability by independently review- using meta-analysis. However, there has been ing each of the cases presented in this study to less enthusiasm for the use of an ECF as a major standardize criteria by which to determine the soft marker for trisomy 21. Likelihood ratios have existence of ECF Regarding technical factors, we . been reported ranging from 1.4 to 2.8.15 Maternal are well aware that thin, small patients allow for weight may prove to be an important factor in the use of higher-frequency transducers, which detecting an ECF in the fetal heart. An ECF in the will increase the detection of ECF A cardiac- . fetal heart of a thin woman may have little apex-up fetal position will do the same. We tried importance. Race has also been shown to affect to avoid these pitfalls. the importance of the finding.16 The single case of trisomy 21 with ECF-1 was In most series, the usual recommendation our earliest detection at 15 weeks 1 day and had when finding a second-trimester fetal ECF is to a single ECF of moderate intensity (Figure 3). Of correlate it with biochemical markers, maternal the ECF-2-associated fetuses with trisomy 21, age, and level II obstetric sonography. Our results there were 2 cases that showed bright ECF and 4 suggest that a finding of multiple ECF is a cases showing moderate ECF (Figure 4). In stronger predictor of trisomy 21 than described reviewing the past literature detailing the nature for a single ECF However, the finding needs to be . of ECF definitions often include that the ECF , put in the context of the situation, and if a patient should match the intensity of fetal bone. has both a high risk for trisomy 21 and multiple Echogenicity is a continuum and dependent on ECF the fetus may have well greater than a 50% , the transducer frequency, depth, and angle of chance of having trisomy 21. insonation. Thus, it is hard to place echogenic appearance in discrete categories. We chose to References separate out a group in which the ECF was not as bright or brighter but did overlap with the 1. Allan LD. Manual of Fetal Echocardiography. London, England: MTP Press; 1986:134. echogenicity of bone. Had we used the strictest definition, we could have missed more than half 2. Brown DL, Roberts DJ, Miller WA. Left ventricular echogenic focus in the fetal heart: pathologic correlation. of the cases of trisomy 21 identified. J Ultrasound Med 1994; 13:613–616. 1066 J Ultrasound Med 2010; 29:1061–1067

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Single Versus Multiple Echogenic Foci in the Fetal Heart

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