Article

An Isolated Echogenic Heart Focus Is Not an Indication for Amniocentesis in 12,672 Unselected Patients
Claudio Coco, MD, Philippe Jeanty, MD, PhD, Cerine Jeanty

Objective. To evaluate the risk of Down syndrome in fetuses with a heart echogenic focus using the Bayes theorem and likelihood ratios in an unselected population. Methods. We prospectively evaluated 12,672 second-trimester sonographic features and extracted and examined a population with an echogenic focus for chromosomal anomalies. Results. There were 479 cases of echogenic focus; 90.4% were isolated, whereas 9.6% had associated findings. Eleven patients had fetuses with trisomy 21 (9 per 10,000). Eight of those did not have an echogenic focus, whereas 3 had a heart echogenic focus. Only 1 fetus with trisomy 21 had an isolated echogenic focus. The positive likelihood ratio for total cases of a heart echogenic focus and trisomy 21 was 7.25, whereas for an isolated echogenic focus, the positive likelihood ratio was 2.66. Conclusions. The results of the statistical analysis showed that the risk of aneuploidy is increased in fetuses with an echogenic intracardiac focus; however, the finding should prompt a detailed structural survey and correlation with a priori risk. Amniocentesis need not be offered to patients who are otherwise at low risk and have an isolated echogenic intracardiac focus. Key words: echogenic heart focus; prenatal diagnosis; soft sign; trisomy 21; unselected population.

A
Received November 12, 2003, from the Department of Ultrasound, Woman's Health Alliance, Nashville, Tennessee USA. Revision requested November 24, 2003. Revised manuscript accepted for publication January 22, 2004. Address correspondence to Claudio Coco, MD, Artemisia Groups, Viale Liegi 49, 00198 Rome, Italy. E-mail: claudio.coco@virgilio.it.

cardiac echogenic focus does not have histopathologic significance. The only consistent histologic finding is mineralization within the papillary muscle. Various works have shown that there is no correlation between a cardiac echogenic focus and heart pathologic anomalies13; therefore, an echogenic focus should be considered a normal physiologic variant. Persistence after birth is not associated with notable cardiac anomalies.4,5 In 1994, Brown et al1 reported that a cardiac echogenic focus could be associated with trisomy 21. This had actually been described in earlier articles in the pathology literature but had not caught the attention of the ultrasound community. Numerous studies have attempted to quantify the risk of the association between a cardiac echogenic focus and trisomy 21, as well as the frequency of the finding. Although most authors suggest that the presence of a cardiac echogenic focus increases the risk for aneuploidy, it is not clear that the increase in risk may justify the performance of amniocentesis.

2004 by the American Institute of Ultrasound in Medicine J Ultrasound Med 23:489496, 2004 0278-4297/04/$3.50

Isolated Echogenic Heart Focus

The purpose of this study was to assess the frequency of cardiac echogenic foci and whether risk and pregnancy management recommendations derived from academic bases, and thus possibly enriched in abnormal cases, are applicable to an unselected base population.

Materials and Methods

Patients of all ages were included in the study, with an average age of 27.2 years, a median of 27 years, and a range of 15 to 42 years (Figure 1). In this group, 11,113 patients (87.70%) were 35 years old or younger when the examination was done; 1559 (12.30%) were older then 35 years. As can be seen in Figure 1, the data follow a normal gaussian distribution. Follow-up information in all cases was obtained by amniocentesis, infant postnatal reports, or contact with the referring physician or pediatrician. If these options failed, the mother was interviewed. From the 16,272 midgestation patients referred to our center from January 1998 to December 2002, 12,672 with a first examination between 16 and 23 gestational weeks were included in the study. The other patients were removed because
Figure 1. Age distribution of the patients.

their initial examinations did not fall within the 16- to 23-week frame. Because this was a first examination (nuchal translucency evaluation was not practiced at that time), none of the patients had first-trimester aneuploidy screening; thus the prevalence of aneuploidy in our population is not biased (Figure 2). Our baseline examination was quite thorough, and aside from American Institute of Ultrasound in Medicine and American College of Radiology guidelines, we attempted to find as many soft markers as possible in all pregnancies. The following is a list of the anomalies that we looked for in all patients. Of course, depending on body habitus and fetal position, not all the markers could be seen. For the most significant one, there were usually no problems (short long bones or nuchal thickness), but more subtle markers such as the simian crease were only looked at for a few seconds and, if not seen, simply passed over. For the head and neck, we looked for brachycephaly, a strawberry-shaped head (flat occiput), wormian bones, a choroid plexus cyst, dysgenesis of the corpus callosum, and nuchal fold thickness. For the face, we looked for macroglossia, micrognathia, a cleft (face, lip, and anterior palate), a flattened midface, a low nasal bridge (we used to

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look in a coronal section of the eyes and nasal bridge, but about 2 years ago we switched to the current sagittal section of the nasal bone), and hypotelorism or hypertelorism. For the last 2 years, we have made modest attempts to look at low-set ears on 3-dimensional sonography, but typically we found them difficult to see in the 18to 22-week period, and at first only 1 of our scanners was capable of doing 3-dimensional imaging, so that was a very minor contributor. For the skeleton, we looked for 11 pairs of ribs, hypoplasia of the clavicle, a double ossification center of the manubrium, short long bones, a wide angle of the iliac wing, hand anomalies (syndactyly, clinodactyly, brachymesophalangia of the fifth digit, simian crease, clenched fist, and radial ray aplasia), and feet anomalies (clubfoot, rocker-bottom foot, sandal gap, and elevation of the first toe). For the abdomen, we looked for echogenic bowel, pyelectasis, and a single umbilical artery. For outflow tracts, we looked for return of pulmonary veins to the left atrium, and, when possible, both arches were also part of the routine. All examinations were performed with Acuson 128XP and Sequoia systems (Siemens Medical Solutions, Mountain View, CA) or a Voluson 730 system (GE Medical Systems, Milwaukee, WI). The results only included data from 2-dimensional examinations, not from 3-dimensional examinations. If an intracardiac echogenic focus was visible in several views with different angles and at different moments in the examination, we considered it to be an echogenic focus. (Our practice was to have second-trimester patients scanned both by experienced sonographers and by a physician.) This eliminated the risk of a specular artifact arisFigure 2. Percentage of population selected.

ing from the chordae tendineae being misconstrued as an echogenic focus. Furthermore, the moderator band often appeared very echogenic in apical or basal orientations of the heart, and, of course, these were not taken into account. The echo amplitude of the heart echogenic focus was compared with that of the thoracic spine. A heart echogenic focus was considered present when there was a discrete dot in either cardiac ventricle as bright as adjacent bone. The echo amplitude of the heart echogenic focus was compared with that of the thoracic spine and in the same intensity. We considered only those echogenic foci that were visible on different angles and by 2 observers to make sure that we did not include specular reflections of papillary muscles (Figure 3). Because the prognostic value of the side of the echogenic focus (left versus right) and the number are unclear from the literature, we lumped together all cases. The maximum number of echogenic foci in a single heart was 5: 3 in the left ventricle and 2 in the right. The cases with a cardiac echogenic focus were selected from these 12,672 cases and further divided into those with an isolated cardiac echogenic focus and those with a cardiac echogenic focus and other major or minor anomalies. During this process, cases of aneuploidy that occurred independently from a cardiac echogenic focus were also noted.

Figure 3. Case with echogenic foci (arrows 14).

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Results
Of the 12,672 patients included in the study, 479 had an echogenic heart focus, which was 3.8% (479 of 12,672) of the total population (Table 1). This was a prevalence of approximately 1 fetus with a cardiac echogenic focus per 26. In our study, 3 of the fetuses with a cardiac echogenic focus had trisomy 21, which was 0.63% (3 of 479). This was equivalent to a prevalence of 62.6 per 10,000, which was 6.8 times higher than the value reported by the Centers for Disease Control and Prevention register of birth defects in Atlanta, Georgia, a large metropolitan region close to our city: 9.2 per 10,000 (range, 5.912.3 per 10,000 in a cohort of 7.8 million births).6 Of the 479 patients with a cardiac echogenic focus, 433 had an isolated cardiac echogenic focus, which was 90.4% (433 of 479; Table 2). Trisomy 21 was identified in only 1 of these cases, which was a prevalence of 1 per 433 or 0.23% for the entire nonage-adjusted cohort. The patient was 35 years old. The number of cases of cardiac echogenic foci associated with other major or minor anomalies was 46, which was 9.6% of the total population; 6 of these cases had major anomalies present, whereas 40 had minor anomalies. There were 2

Table 1. Distribution of the Echogenic Heart Focus Found in This Study

Total Patients 12,672 Patients

cases of trisomy 21: 1 with minor associated anomalies present and the other with major associated anomalies, which was a prevalence of 1 per 23 or 4.3%. The first case of trisomy 21 included 2 additional minor sonographic findings: bilateral pyelectasis and a sandal gap on the right foot. The mother was 23 years old. In the second case of trisomy 21, the other findings included hydrocephalus, brachycephaly, hypoplasia of the fifth digit, and a 2-vessel cord (Table 3). Other types of aneuploidy noted in the total population were 6 cases of trisomy 18, 2 trisomy 13, 1 triploidy, 2 monosomy X, 1 triple X, and 1 ring 14 chromosome. None of these patients had a cardiac echogenic focus. Eight patients had trisomy 21 in the absence of an echogenic heart focus, which was 0.066% of the population examined (8 of 12,193). The prevalence of trisomy 21 and 18 in the population examined was similar to that in the base population. In our population, the prevalence of trisomy 18 was 4.7 per 10,000, which was similar to the accepted rate of 2.8 per 10,000 calculated from the register of birth defects at the Centers for Disease Control and Prevention.6 The prevalence of trisomy 21 in our population was 9 per 10,000, which was similar to the accepted figure of 9.2 per 10,000. The sex of 428 fetuses with cardiac echogenic focus was noted: 226 were male (53%) and 202 were female (47%). This indicates that there was no sexual preponderance. Figure 4 shows the details of the population examined.

Total patients with echogenic heart focus, n Echogenic heart focus among total patients, % Echogenic heart focus with no other anomalies, n Echogenic heart focus with no other anomalies among total echogenic heart focus, % Echogenic heart focus and associated anomalies, n Echogenic heart focus and associated anomalies among total echogenic heart focus, %

479 3.80 433 90.4 46 9.6

Discussion
In our study, conducted in an unselected population, the prevalence of trisomy 21 among fetuses with an echogenic heart focus (3 per 479 [0.626%]) was higher than the prevalence of trisomy 21 among fetuses without an echogenic heart focus in the whole population of fetuses without an echogenic heart focus: 8 per 12,193 (12672 total cases 479 fetuses with an echogenic heart focus) or 0.0656%. This is equivalent to a positive likelihood ratio of 7.25 (Table 4). We think that there was an overlap of risk in these data because in 2 cases there were other markers of aneuploidy. The statistical analysis for the different groups shows that the real risk is much less for an isolated heart echogenic focus.

Table 2. Aneuploidy Present in the 2 Groups

Group No. of Patients

Fetuses with an isolated echogenic cardiac focus Normal Aneuploidy Fetuses with a cardiac echogenic focus and other sonographic findings Normal Aneuploidy

432 1 (trisomy 21)

44 2 (both trisomy 21)

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Table 3. Details of the Cases of Trisomy 21 Identified in the Population Examined, Focusing on a Cardiac Echogenic Focus and Other Associated Anomalies
Case Karyotype Echogenic Cardiac Focus Other Findings Maternal Age, y

1 2 3 4 5

Trisomy 21 Trisomy 21 Trisomy 21 Trisomy 21 Trisomy 21

Yes Yes No No No

6 7 8 9 10 11

Trisomy 21 Trisomy 21 Trisomy 21 Trisomy 21 Trisomy 21 Translocation 14-21

No No No Yes No No

Sandal gap on the right foot, bilateral pyelectasis Hydrocephalus, brachycephaly, hypoplasia of the 5th digit, 2-vessel cord 2-vessel cord None Omphalocele, mild ventriculomegaly, microphthalmia, micrognathia, short femur Abdominal calcification None None None None Pyelectasis

23 30 32 39 33

34 33 42 35 44 23

Bayesian Analysis Because sensitivity, specificity, positive predictive value, and negative predictive value depend on the prevalence of the disease and of the markers in the population, Bayesian theory is necessary to perform the calculations: prevalence, 0.0009; sensitivity, 0.2727; specificity, 0.9624; positive predictive value, 0.0063; negative preFigure 4. Details of the population examined.

dictive value, 0.993; positive likelihood ratio, 7.2542; and negative likelihood ratio, 0.7557. According to the Bayes theorem, the probability of trisomy 21, given a prior probability of 0.09% and the sonographic finding of an echogenic heart focus, would be (27.27% 0,09%)/[(27.27% 0,09%) + (3.91% 99,93%)] = 0.60%. Likewise, the probability of not having the condition,

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given the occurrence of a negative finding, would be (97.6% 99.91%)/[(97.6% 99.91%) + (2.4% 0.09%)] = 99.99%. However, of the 3 fetuses with trisomy 21 and echogenic heart focus, 2 had other findings suggestive of trisomy 21 (a sandal gap and bilateral pyelectasis in 1 and hydrocephalus, brachycephaly, hypoplasia of the fifth digit, and a 2-vessel cord in the other). Thus, if these 2 fetuses were taken out, the likelihood of a fetus with trisomy 21 among fetuses with an echogenic heart focus and no other findings would drop to 1 per 433 (479 total cases of fetuses with echogenic focus 46 cases with associated anomaly). We then modified Table 4 to Table 5: prevalence, 0.0009; sensitivity, 0.0909; specificity, 0.9659; positive predictive value, 0.0023; negative predictive value, 0.9992; positive likelihood ratio; 2.6644; and negative likelihood ratio, 0.9412 The Bayesian analysis in these cases would be as follows: in the presence of an isolated heart echogenic focus, (9.09% 0,09%)/[(9.09% 0.09%) + (3.53% 99.92% )] = 0.22%; in the absence of a heart echogenic focus, (96.59% 99.92%)/[(96.59% 99.92% ) + (3.53% 0.09% )] = 99.9968%. Comparison With Other Studies Many other studies we examined agree that the presence of an echogenic heart focus does not warrant amniocentesis. In a population of patients who underwent amniocentesis, Caughey et al7 determined that the risk of fetal loss due to miscarriage outweighs the benefits of identifying a fetus with trisomy 21. Huggon et al8 suggested that the prior risk is increased by a factor of 3, which is very similar to our value of 2.6. Winter et al9 calculated that the prior risk in their high-risk population was increased

Table 4. Statistical Analysis for Total Cases of Trisomy 21 and Echogenic Heart Focus (2 2 Table)
Total Cases: 12,672 Trisomy 21 Normal

Echogenic heart focus Absence of echogenic heart focus

True-positive: 3 False-negative: 8

False-positive: 476 True-negative: 12,185

Table 5. Statistical Analysis for Isolated Echogenic Focus (2 2 Table)

Total Cases: 12,672 Trisomy 21 Normal

Isolated echogenic heart focus Absence of echogenic heart focus

True-positive: 1 False-negative: 10

False-positive: 432 True-negative: 12,229

4.8-fold. In a study by Bettelheim et al,10 there were several cases of aneuploidy in the group with associated sonographic findings, whereas in the group with an isolated echogenic heart focus, there was only 1 case of aneuploidy (a 46,XX/45,X0 mosaic). A meta-analysis by Sotiriadis et al11 showed an incidence of approximately 4% of echogenic heart foci in fetuses with no abnormalities, which was comparable to our results (3.8%). They calculated an average likelihood ratio of 6.2: when the echogenic heart focus was in association with other anomalies, the likelihood ratio was 7.0, and an isolated echogenic heart focus had a likelihood ratio of 5.4. They noted that the observed variability of the study reviewed in the metaanalysis should lead to a cautious interpretation of the findings. Furthermore, most of the included studies were conducted in relatively high-risk populations. In an age-adjusted sonographic risk assessment, Nyberg and Souter12 used a likelihood risk of 1.8. In a study by Anderson and Jyoti,13 isolated heart echogenic foci in women aged 18 to 34 years were not associated with increased risk for trisomy 21 in midgestation. They found 149 cases among 9167 women in this age group, with a prevalence of 1.63%; this result was lower than that in our population (3.78%). Their analysis on all cases of trisomy 21 identified in all age groups led to a result comparable with ours. Among 25 fetuses with trisomy 21, 5 had an echogenic focus (20%; our rate was 27%). One case was isolated. In contrast, Vibhakar et al14 said that the presence of an isolated intraventricular echogenic focus carried a relative risk of 4.08 compared with those fetuses in which sonography yielded no finding associated with aneuploidy. Their population consisted of high-risk referrals, including a presumably enriched population with aneuploidy. Bromley et al15 reported an increased risk among 290 fetuses who had an echogenic intracardiac focus, of whom 14 (4.8%) were aneuploid, and they concluded that the presence of an echogenic intracardiac focus did raise a fetuss risk of having a chromosomal abnormality, most commonly Down syndrome. The population in that study was a mix of high and low risk. Simpson et al16 reported a total of 228 fetuses with an isolated heart echogenic focus, with a prevalence of 6.9% of the total number of fetuses scanned. Karyotypic abnormalities were diagnosed postnatally in 2 of those.
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Wax et al17 suggested that sonographic grading of heart echogenic foci is an important parameter for distinguishing different risks for aneuploidy. We did not do that differentiation. In 25,725 sonographic examinations conducted for fetal malformations between 12 and 24 weeks gestation, Bronshtein et al18 reported a prevalence of 0.17% (44 cases). Whitlow et al19 reported a similar prevalence (0.8%) and a significant association with fetal aneuploidy, especially for trisomy 21, with a positive likelihood ratio of 12.3. Previous works gave results very similar to ours. In a study by Bromley et al,20 the likelihood ratios were 8 in all cases and 1.4 when heart echogenic foci were isolated. A different meta-analysis from Smith-Bindman et al21 yielded a positive likelihood ratio of 2.8 for an echogenic focus as an isolated marker, a value similar to that of Nyberg et al,22 who found a positive likelihood ratio of 1.8. Conclusions In this large study, we examined the prevalence of cardiac echogenic foci in an unselected population. Determining the prevalence in an unselected population is necessary to consider whether a karyotype is warranted. In this study, we found that 3.8% of the 12,672 fetuses examined had a cardiac echogenic focus: 90.4% of these were isolated cases, whereas 9.6% occurred in the presence of other anomalies. Only 3 cases of a cardiac echogenic focus had trisomy 21 (0.63%): 1 had an isolated cardiac echogenic focus, and the other 2 had a cardiac echogenic focus with associated anomalies. The decision to perform amniocentesis is affected by many different factors. In cases with a heart echogenic focus in the presence of other associated major anomalies, performing amniocentesis is warranted. In a case of a 23-year-old patient in whom 2 other minor markers were identified, including sandal gap on the right foot and bilateral pyelectasis, performance of amniocentesis was suggested as well. In another case, a 35-year-old patient had an isolated heart echogenic focus. The normal prevalence for the age group is about 1 per 302 at 20 weeks and 1 per 356 at birth. In summary, an isolated echogenic heart focus is an indication to perform a detailed and accurate examination for other markers of aneuploidy. If the echogenic focus is an isolated finding, it should be assigned a likelihood ratio of 2.6 for Down syndrome, thus providing a more refined patient risk of
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aneuploidy. If this refined risk estimate is below the commonly accepted threshold for offering amniocentesis, then it need not be discussed. If, however, the revised risk is above the threshold, amniocentesis needs to be offered if prenatal diagnosis is desired. If we had performed amniocenteses on all fetuses with an isolated echogenic focus, the fetal loss would have been 2.16, assuming a commonly accepted miscarriage rate of 1 per 200. However, if we restricted amniocentesis to only fetuses with associated findings and a heart echogenic focus, only 46 karyotypes needed to be performed to identify 2 cases of trisomy 21. This would reduce the calculated fetal loss to 0.23 fetuses. Our study indicates that the presence of another major or minor sign with a heart echogenic focus justifies the performance of amniocentesis.

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