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(Radiology. 2000;216:450-456.)
© RSNA, 2000

Obstetric Imaging

Echogenic Intracardiac Focus in 2nd-Trimester Fetuses with Trisomy 21: Usefulness as a US Marker1

Thomas C. Winter, MD, Amy M. Anderson, BSc, Edith Y. Cheng, MD, Cathy A. Komarniski, RDMS, Vivienne L. Souter, MD, Stefanie B. Uhrich, MS, CGC and David A. Nyberg, MD

1 From the Department of Radiology, Division of Ultrasound (T.C.W., A.M.A., C.A.K.), and the Department of Obstetrics and Gynecology, Division of Perinatal Medicine (E.Y.C., S.B.U.), University of Washington Medical Center, Seattle; and Swedish Nuclear Medicine and Ultrasound Associates, Seattle, Wash (V.L.S., D.A.N.). Received May 18, 1999; revision requested July 19; final revision received December 13; accepted January 12, 2000. Address correspondence to T.C.W., Department of Radiology, University of Wisconsin Hospital, E3/311 CSC, 600 Highland Ave, Box 3252, Madison, WI 53792-3252.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
PURPOSE: To determine whether there is a relationship between the presence of an echogenic intracardiac focus in 2nd-trimester fetuses and trisomy 21 (Down syndrome).

MATERIALS AND METHODS: A complete genetic ultrasonographic (US) scan was obtained in 3,303 consecutive fetuses with an estimated gestational age of 14.0–24.0 weeks (mean ± SD, 17.1 weeks ± 1.75). US was performed in a prospective fashion without any knowledge of karyotype and included assessment of any potential echogenic intracardiac focus (ie, calcified papillary muscle). Karyotypes were obtained in all fetuses. Maternal ages ranged from 13.0 to 47.4 years (mean, 35.1 years ± 5.1). The prevalence of Down syndrome in this population was 1.6% (53 of 3,303 fetuses).

RESULTS: An echogenic intracardiac focus was seen in 147 of the 3,192 karyotypically normal fetuses (4.6%) and 16 of the 53 fetuses with trisomy 21 (30%). The positive predictive value (PPV) of an echogenic intracardiac focus in this high-risk population was 9.8%; sensitivity, 30%; specificity, 95%; likelihood ratio, 6.6; and relative risk (RR), 8.2 (P < .001). For a sonographically isolated echogenic intracardiac focus, the PPV was 3.7%; sensitivity, 19%; specificity, 95%; likelihood ratio, 4.2; and RR, 4.8 (P = .002).

CONCLUSION: A sonographically isolated echogenic intracardiac focus (no other anomalies or markers noted on a complete genetic sonogram) was associated in our high-risk population with a 4.8-fold (95% CI: 1.8, 12.5) increase in RR for trisomy 21 (P = .002).

Index terms: Down syndrome, 856.184 • Fetus, abnormalities, 856.8753 • Fetus, US, 856.1298 • Heart, US, 856.8753


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Trisomy 21 (Down syndrome) is the most common karyotype abnormality in liveborn infants (one per 800 livebirths [1]) and one of the leading causes of mental retardation. Historically, diagnostic amniocentesis was offered to women of advanced maternal age (>35 years of age); however, only 20% of fetuses with Down syndrome are born to women older than 35 years (2), prompting searches for better methods of prenatal diagnosis.

One avenue for prenatal diagnosis is fetal ultrasonography (US). Fetuses with Down syndrome have an increased risk for major malformations; however, only a minority of fetuses are affected and an even smaller number of these are detected prenatally. In recent years, a number of US "markers" for trisomy 21 have been identified (see Benacerraf’s excellent review on the use of US markers [3]). These markers are characterized as being (a) nonstructural or not important themselves; (b) nonspecific, found in normal fetuses but with greater frequency among fetuses with Down syndrome; and (c) sometimes transient. US markers include thickened nuchal fold (4–6), mild limb shortening of the humerus and femur (7–12), mild renal pyelectasis (13,14), echogenic bowel (15), flared iliac crest (16–19), and frontal lobe shortening (20).

The echogenic intracardiac focus is another marker that has been associated with Down syndrome, as well as with trisomy 13 (21,22). Originally, the cause and exact location of these foci were uncertain; hence, they have been also known as echogenic chordae tendineae or echogenic papillary muscle. Brown et al (23) showed that the finding of an echogenic intracardiac focus at US correlates with mineralization within a papillary muscle. At the time we wrote this article, we had found 21 publications addressing the echogenic intracardiac focus (21,23–42). The strength of the association of echogenic intracardiac focus with trisomy 21 is controversial, with some authors concluding that there is no association (24,30,33) and others noting an increased relative risk (RR) of 4.3 (25), 7.8 (31), and 19 (35). Combining maternal age with a panel of US markers, termed "age-adjusted US risk assessment for Down syndrome," Nyberg and others (32,43) assigned a RR of 2.0 for echogenic intracardiac focus as an isolated finding. Using an index scoring method, Benacerraf and colleagues (44) assigned a score of 1 to echogenic intracardiac focus and other markers (excluding nuchal thickening, which carries a score of 2), which suggests that the risk of echogenic intracardiac focus is similar to that of other markers.

In an effort to further clarify the potential usefulness of echogenic intracardiac focus as a marker for Down syndrome, we evaluated echogenic intracardiac focus in a prospective series of fetuses who underwent genetic amniocentesis. To our knowledge, this is the largest study that has been performed prospectively and consecutively, with complete karyotype determination, and the only such study where a complete genetic US scan was obtained and evaluated so that the statistical significance of a sonographically isolated echogenic intracardiac focus could be analyzed.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Between February 14, 1996, and August 17, 1998, a complete genetic US scan was obtained in 3,303 fetuses with an estimated gestational age of 14.0–24.0 weeks (mean ± SD, 17.1 weeks ± 1.8). US was performed in a prospective fashion without any knowledge of karyotype and included assessment of any potential echogenic intracardiac focus (ie, calcified papillary muscle). Karyotypes were obtained in all fetuses. Maternal age ranged from 13.0 to 47.4 years (mean ± SD, 35.1 years ± 5.1). These fetuses had been referred to undergo amniocentesis and US at the two largest high-risk centers in Seattle, Wash, with 1,814 from the University of Washington (February 14, 1996, through August 17, 1998, ~724 per year), and 1,489 from the Swedish Medical Center (May 3, 1996, through June 26, 1998, ~693 per year). All consecutive fetuses at each institution who met the study criteria (gestational age between 14.0 and 24.0 weeks and complete, prospectively performed genetic US and subsequent karyotyping) were included; to ensure that this was a true prospective study, no fetuses with echogenic intracardiac focus or any other finding were added to this population after the fact.

The complete genetic US scan was obtained according to American Institute of Ultrasound and Medicine guidelines (45) (with additional evaluation of the posterior fossa and outflow tracts and the presence of all long bones in the extremities, hands, and feet and a coronal view of the nose and lips attempted whenever possible). In addition, scans were assessed for structural anomalies, a nuchal skin fold at least 6 mm thick (4), pyelectasis of at least 4 mm in diameter (13), femoral and humeral limb length ratios (46), echogenic bowel of grade II or III (15), choroid plexus cysts, and echogenic intracardiac focus. An echogenic intracardiac focus (Figure) was considered present if an echogenic focus as bright as bone was seen in the region of the papillary muscle of the fetal heart, regardless of ventricular side or multiplicity. As expected, however, the vast majority of echogenic intracardiac foci were solitary and located in the left ventricle.



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  		Figure 1. Transverse US scan of the fetal chest demonstrates a solitary echogenic intracardiac focus (arrow) in the left ventricle.

 
Each US examination was performed by a board-certified radiologist (including T.C.W. and D.A.N.). Each radiologist had undergone additional specialty training in high-risk obstetric US. Although data were collected regarding choroid plexus cysts, they were not included in the analysis because findings of two recent studies have shown no statistically significant association between Down syndrome and choroid plexus cysts (26,47).

Calculations (48) were performed with the use of MATHCAD PLUS, version 6 (MathSoft, Cambridge, Mass). The cumulative binomial distribution function was calculated by using SYSTAT (Systat, Evanston, Ill). The Fisher exact test ({chi}2 approximation when the numbers were too large for the Fisher exact test) and the approximation of Katz (for 95% CI for RR) were calculated by using INSTAT, version 2.03 (GraphPad Software, San Diego, Calif).

Sensitivity is also known as the true-positive rate and is written as P(T+|D+), the probability of a positive test result given a diseased patient, or with the formula TP/(TP + FN), where TP is the number of true-positive findings and FN is the number of false-negative findings. Specificity is also known as the true-negative rate and is written as P(T-|D-), the probability of a negative test result given a healthy patient, or with the formula TN/(TN + FP), where TN is the number of true-negative findings and FP is the number of false-positive findings. By using similar notation, the positive predictive value (PPV) is P(D+|T+) = TP/(TP + FP), and the negative predictive value is P(D-|T-) = TN/(FN + TN). The false-positive rate is P(T+|D-) = FP/(FP + TN), and the false-negative rate is P(T-D+) = FN/(TP + FN).

The likelihood ratio was defined as sensitivity divided by the false-positive rate or as sensitivity/(1 - specificity). This can be written as [P(T+|D+)]/[P(T+|D-)], the probability of a positive test result in the group with disease divided by the probability of a positive test result in the control group, which equals (TP/FP) x [(FP + TN)/(TP + FN)]. The RR is defined as PPV/(1 - negative predictive value). This can be written as [P(D+|T+)]/[P(D+|T-)], or the probability of disease in a group with a positive test result divided by the probability of disease in a group with a negative test result, which equals (TP/FN) x [(FN + TN)/(TP + FP)]. Intuitively, disease occurs RR times as often in the group with positive test results (eg, if the RR is 2.0, disease occurs twice as often in the group with positive test results). The RR may be used with prospective or cross-sectional studies but is entirely meaningless with retrospective studies (Motulsky HT, help menu on test interpretation, INSTAT for Macintosh, GraphPad Software, 1994). For calculations of the RR and the PPV in the general (low-risk) population, the following equations were used (and sensitivity and specificity were assumed to be unchanged between low- and high-risk populations): PPV = (P x sensitivity)/[(P x sensitivity) + (1 - P)(1 - specificity)], and RR = {[P x (1 - sensitivity - specificity) + specificity] x sensitivity}/{[P x (sensitivity + specificity - 1) + (1 - specificity)] x (1 - sensitivity)]}, where P is disease prevalence.

PPV, the positive screening rate, and RR depend heavily on the disease prevalence. Indeed, many question the value of results of studies obtained from high-risk populations when applied to a low-risk group (49). The second-trimester, low-risk disease prevalence for the purposes of PPV, positive screening rate, and RR calculations for this study was estimated at one in 600, as follows. Cuckle et al (50,51) combined data from eight surveys about a total of 3,289,114 births to determine the prevalence of trisomy 21 at each maternal age, resulting in a regression curve showing the familiar exponential increase in prevalence of trisomy 21 with increasing maternal age in years (0.000627 + exp[-16.2395 + 0.286 x age]). The prevalence of Down syndrome at birth in the general population has been estimated at anywhere between one in 600 to one in 1,000 births (1,52,53), with one in 800 being perhaps the most commonly quoted and accurate value (1,51,54). According to Snijders et al (51), the relative prevalence of trisomy 21 at an estimated gestational age of 17 weeks is approximately 1.4 times that at term (there is a loss of Down syndrome fetuses between 17 weeks and term). Koulischer and Gillerot (54) determined the overall incidence at birth of Down syndrome to be one in 813. Therefore, 1.4 x (1/813) = 1/574, which is approximately 1/600.

To obtain larger numbers of patients for the purposes of statistical analysis, an analysis of our data was performed in conjunction with those from two other studies (25,31), where echogenic intracardiac focus was prospectively assessed and karyotype data were obtained in all patients (the analysis is not entirely accurate because Bromley et al [25] compared fetuses with trisomy 21 with fetuses without trisomy 21 [not necessarily euploid]; however, the results should not be substantially affected because the prevalence of other chromosome anomalies was quite low). Manning et al (31) did not report specific karyotypes, just trisomy 21 and normal. This constitutes an analysis of high-risk groups.

Another published study (33) met these criteria but yielded slightly surprising results. Specifically, there were no cases of trisomy 21 in their population. Populations in which amniocentesis is performed are, in general, at high risk. In the study by Petrikovsky et al (33), more than half of their patients (512 of 1,139) were referred for amniocentesis because of advanced maternal age. Other indications for amniocentesis included abnormal maternal serum {alpha}-fetoprotein level (n = 169), prior child born with chromosomal anomaly (n = 12), and miscellaneous (n = 446). The second-trimester prevalence for Down syndrome in the high-risk populations in the two studies included in this analysis were 1.6% (25) and 1.9% (31). The prevalence of Down syndrome in our high-risk population was 1.6% (53 of 3,303 fetuses). With a prevalence of 1.6%, one would expect 18.2 fetuses with trisomy 21 in the study by Petrikovsky et al (33). It is not until the prevalence is less than 0.265% (one of 377 fetuses), which is close to the general low-risk population risk of one of 600 fetuses, that it is statistically feasible (P >= .05, cumulative binomial distribution function) to have no fetuses with Down syndrome in a population of 1,139 fetuses. Therefore, because we are unsure as to why they had a 0% prevalence of Down syndrome in their high-risk population, we made the decision to exclude their data from the analysis of similar trials.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
In our study, 3,192 fetuses had euploid (1,555 with 46,XX; 1,615 with 46,XY) or phenotypically normal (22 with balanced translocations, inversion 9, or other) karyotypes, 53 had trisomy 21, 10 had trisomy 18, six had trisomy 13, eight had sex chromosome abnormalities, seven had triploidy, six had monosomy X, and 21 had other potentially clinically important karyotypes.

The prevalence of Down syndrome in this high-risk population was 1.6% (53 of 3,303 fetuses). The mean gestational age of the 53 fetuses with Down syndrome was 17.2 weeks ± 1.8, and the mean gestational age of the 3,192 karyotypically normal fetuses was 17.1 weeks ± 1.7. The mean maternal age for the 53 fetuses with Down syndrome was 35.0 years ± 6.1, and the mean maternal age for the 3,192 karyotypically normal fetuses was 35.2 years ± 5.0. The mean estimated gestational age difference of 0.1516 weeks between the 3,192 karyotypically normal fetuses (mean gestational age, 17.09 weeks) and the 53 fetuses with trisomy 21 (mean gestational age, 17.24 weeks) was not statistically significant (P = .54, Student t test for independent samples). The mean maternal age difference of 0.1245 years between the 3,192 fetuses with normal karyotypes (mean maternal age, 35.16 years) and the 53 fetuses with trisomy 21 (mean maternal age, 35.03 years) was not statistically significant (P = .88, Student t test for independent samples).

Of the 53 fetuses with trisomy 21, 16 (30%) had an echogenic intracardiac focus. In five of those 16 fetuses (31%), the echogenic intracardiac focus was the only finding on the complete genetic US scan. If limb ratios are excluded (as some institutions do not calculate limb ratios), the echogenic intracardiac focus was the only US finding in six of the 16 fetuses (38%) with trisomy 21 and an echogenic intracardiac focus. Of the five fetuses with trisomy 21 and a sonographically isolated echogenic intracardiac focus, four mothers were older than 35 years at delivery. The remaining mother was 34.7 years of age at delivery; however, the results of 16.3-week "triple screen" (analysis of {alpha}-fetoprotein, human chorionic gonadotropin, and unconjugated estriol levels) indicated that she had a calculated risk for Down syndrome of one in 140 (higher than threshold; ie, amniocentesis was warranted on the basis of the pregnancy risk profile [triple screen]). The mother of the sixth fetus, whose genetic sonogram showed an echogenic intracardiac focus and an abnormally short femur, was 40.2 years of age at US. In comparison, of the 3,192 fetuses with a normal karyotype, 147 had an echogenic intracardiac focus, which was an isolated finding in 130 of the 147 fetuses (88%).

The Table gives detailed results regarding the relationship between trisomy 21 and echogenic intracardiac focus. First, we present our data regarding the association of echogenic intracardiac focus and trisomy 21 regardless of whether other US anomalies were present and regardless of maternal age. This analysis is similar to that performed for the other three studies listed. Our data help confirm a significantly high association between echogenic intracardiac focus and trisomy 21, with a PPV in the high-risk population of almost 10%, a sensitivity of 30%, a likelihood ratio of 6.6, and an RR of 8.2. Analysis of our results with those of Manning et al (31) and Bromley et al (25) yields a study with 5,480 second-trimester fetuses with proved karyotype and prospectively obtained US scans and has very similar statistical results to our subset of the data.

For a sonographically isolated echogenic intracardiac focus, the PPV decreases to 3.7%, sensitivity to 19%, likelihood ratio to 4.2, and RR to 4.8. Again, this was statistically significant (P = .002, Fisher exact test). Exclusion of humeral and femoral ratios in the analysis does not substantially change the results.

The final analysis is of the subset of women who were 35 years of age or younger at delivery (ie, at low risk according to age criteria) and who had a sonographically isolated echogenic intracardiac focus. Results did not reach statistical significance in this category owing to the small number of cases in the true-positive cells of the contingency table. The analysis was done twice—once including limb ratios and once excluding limb ratios—but the results were not very different. Specifically, the PPV was 2.0%; sensitivity, approximately 8%; likelihood ratio, approximately 1.5; and RR, approximately 1.5.

Six of the fetuses had trisomy 13. Three of the six fetuses (50%) had an echogenic intracardiac focus, but all three had other substantial structural anomalies that were very worrisome for aneuploidy independent of the echogenic intracardiac focus. Ten of the fetuses had trisomy 18. One of these 10 fetuses (10%) had an echogenic intracardiac focus along with multiple other structural anomalies.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The results of our study of high-risk patients help confirm that echogenic intracardiac focus is associated with fetal aneuploidy, especially trisomies 21 and 13. In the largest prospective series of echogenic intracardiac focus in high-risk patients to date that includes complete genetic US and karyotype ascertainment, we found an echogenic intracardiac focus in 50% (three of six) of fetuses with trisomy 13 and 30% (16 of 53) of fetuses with trisomy 21. It is important to note that isolated echogenic intracardiac focus without other US markers was also associated with trisomy 21 (P = .002; RR, 4.8; likelihood ratio, 4.2).

The results of our study helped confirm those of two similarly structured studies (25,31), which demonstrated a strong association between echogenic intracardiac focus and trisomy 21. The PPV in our high-risk population was almost 10%, sensitivity was 30%, likelihood ratio was 6.6, and RR was 8.2. In a third study (33), the authors found no association between echogenic intracardiac focus and trisomy 21 and concluded that the echogenic intracardiac focus is a normal variant. For reasons discussed earlier, however, their series of 1,139 fetuses presumed to be at high risk appeared to be statistically anomalous in that there was a 0% prevalence of trisomy 21. Absence of any fetuses with trisomy 21 makes it difficult to compare echogenic intracardiac focus in the euploid population and the Down syndrome population.

Although the above association is interesting, it is less than clinically useful because the parents of a fetus with an echogenic intracardiac focus and other structural anomalies or markers are usually easily counseled about the relative benefits of amniocentesis. Similar results were noted in the subset of our data, where we looked at fetuses with trisomy 18 and trisomy 13. These karyotypically abnormal fetuses with an echogenic intracardiac focus all had other substantial structural or multiple marker anomalies that would prompt amniocentesis even in the absence of an echogenic intracardiac focus. What would be much more useful clinical information is the association between a sonographically isolated echogenic intracardiac focus and trisomy 21. In our high-risk population, a sonographically isolated echogenic intracardiac focus (ie, no other anomalies or markers were noted on a complete genetic US scan) was significantly associated with trisomy 21 (P = .002), with a 4.8-fold (95% CI = 1.8, 12.5) increase in RR. The PPV was 3.7%; sensitivity, 19%; specificity, 95%; and likelihood ratio, 4.2. The exclusion of limb ratios did not change these results significantly.

Probably the most useful clinical information would be data addressing the association of trisomy 21 in the low-risk patient with an isolated echogenic intracardiac focus. Specifically, what is the RR if maternal age is less than 35 years, the results of a triple screen are normal, and there are no other risk factors? Our study did not have enough statistical power to reach a definitive conclusion in this area. For an isolated echogenic intracardiac focus when maternal age was less than 35 years, the PPV was 2.0%; sensitivity, approximately 8%; likelihood ratio, approximately 1.5; and RR, approximately 1.5 (95% CI = 0.21, 12.4). Again, the exclusion of limb ratios did not substantially change these results. Our solitary patient who was not of advanced maternal age but who had an isolated echogenic intracardiac focus was also judged to be at high risk on the basis of her triple screen results. It is unknown whether echogenic intracardiac focus is associated with abnormal maternal serum biochemistry.

The strengths of this study are twofold. First, this is to our knowledge the largest prospective study with complete genetic karyotype ascertainment in which the association between echogenic intracardiac focus and aneuploidy were investigated. The 3,303 fetuses studied represent almost 2.5 times more fetuses than the next largest study with karyotype ascertainment (Bromley et al [25] studied 1,334 fetuses; Petrikovsky et al [33] studied 1,139; and Manning et al [31] studied 901). Second, and probably more important, this is to our knowledge the only study with complete karyotype ascertainment where formal genetic US was prospectively and consecutively performed and reported on so that the importance of an isolated echogenic intracardiac focus could be statistically analyzed.

The major weaknesses of this study are also twofold. First, and probably most important, our data come from a high-risk group. All of our patients were referred for amniocentesis on the basis of one or more of the following indications: advanced maternal age (age at delivery, >35 years), abnormal pregnancy risk profile (on the basis of results of the triple screen), high or low maternal serum {alpha}-fetoprotein level, maternal anxiety, teratogen exposure, or positive family history for a previous fetal malformation. The mean maternal age in our population was 35.1 years.

Even with 3,303 fetuses, the prevalence of a truly sonographically isolated echogenic intracardiac focus was so low that conclusions did not reach statistical significance in the important low-risk subset of this group where maternal age was 35 years or younger. Unfortunately, the definitive study in a general low-risk population with complete accurate karyotype ascertainment, quality US scans, and large enough numbers to reach statistical significance may never be performed. Relying on data other than karyotype to determine the presence of trisomy 21 in the general population is fraught with difficulty. For example, studies of infants with Down syndrome have demonstrated that the condition is not entered on the birth certificate in 50%–70% of cases (51).

The second major weakness is the subjective nature of what constitutes an echogenic intracardiac focus. Unlike structural defects (eg, endocardial cushion defect) or measurable quantities used as markers for Down syndrome, such as limb lengths (46) or frontothalamic diameter (20), an echogenic intracardiac focus is a more qualitative assessment that depends on equipment, the observer’s threshold and definition, and whether studies were performed prospectively or retrospectively. Additional uncertainty about the importance of an echogenic intracardiac focus is introduced by the fact that echogenic intracardiac focus visualization may depend on the orientation of the four-chamber view (55) and that the prevalence of echogenic intracardiac focus may be significantly higher among Asian mothers as opposed to mothers of other races (56). A wide range in the prevalence of echogenic intracardiac focus has been reported in the literature to date, from 0.17% in a retrospective study of 25,725 fetuses (27) to 20% in a prospective study of 118 fetuses (30). Most estimates cluster around 3%–7% (24,28,36,39). Analysis of three previously published prospective studies with karyotype ascertainment and our current study yielded a prevalence for echogenic intracardiac focus in the normal second-trimester fetus from a high-risk population of 4.2% (271 of 6,527, which is the sum of 62 of 1,312 [25], 21 of 884 [31], 41 of 1,139 [33], and 147 of 3,192). A grading system similar to that proposed for echogenic bowel may be useful for standardizing this assessment.

The crucial question that remains to be answered is the potential importance of a sonographically isolated echogenic intracardiac focus in the low-risk patient (young and with normal triple screen results). This may prove to be a formidable task to perform in a rigorous and scientific fashion, because high-quality genetic US (often, it is only high-risk women who are referred to tertiary care centers where the necessary US expertise is available and results of studies are published) and complete and accurate karyotype follow-up must be performed in all of these low-risk patients (as mentioned previously, studies of infants with Down syndrome have shown that the condition is not entered on the birth certificate in 50%–70% of cases [51]). Achiron et al (24) concluded from an examination of 2,214 low-risk pregnancies that karyotyping is unwarranted in the second-trimester fetus with incidental findings of an echogenic intracardiac focus; however, only 16 of 66 fetuses with echogenic intracardiac focus in their study underwent karyotyping.

In Bromley et al’s (42) series of 14 aneuploid fetuses with echogenic intracardiac focus, only one had a sonographically isolated echogenic intracardiac focus; the maternal age for this fetus was 41 years. In addition, not all of the fetuses in their series underwent karyotyping. Petrikovsky et al (33) studied 1,139 fetuses, all of whom underwent karyotyping; 3.6% had an echogenic intracardiac focus. There were no cases of trisomy 21 in their series.

Simpson et al (39), in a low-risk population, attempted to specifically address this important issue in 205 fetuses with echogenic intracardiac focus and no other US abnormalities (they did not specify whether limb ratios were calculated). Follow-up ascertainment, however, was provided by means of a standard questionnaire filled out by the parents when the baby was 6 weeks old. Two of these fetuses had chromosomal anomalies (one had trisomy 21, and one had unbalanced translocation). Therefore, Simpson et al counsel low-risk patients that an isolated echogenic intracardiac focus has a 1% risk for genetic abnormality.

We did not investigate any potential difference in the importance of multiple, bilateral, or right-sided echogenic intracardiac focus as markers for trisomy 21 when compared with the typical unilateral single left ventricular echogenic intracardiac focus (27,34,40,42). Another issue not addressed in this study is the potential cardiac structural importance of an echogenic intracardiac focus (27–30,36–39). It is our standard practice to counsel patients that the typical echogenic intracardiac focus has no structural importance whatsoever and that if the karyotype is normal the echogenic intracardiac focus has no bearing on the future health of the fetus.

In summary, an echogenic intracardiac focus is definitely associated with fetal aneuploidy, especially trisomies 21 and 13. We present the results of, to our knowledge, the largest series to date where complete consecutive prospective genetic US scans were obtained from a population who all underwent amniocentesis. In this high-risk population, an echogenic intracardiac focus was definitely associated with trisomy 21, with a likelihood ratio of 6.6, RR of 8.2, and PPV of 9.8% (P < .001). For a sonographically isolated echogenic intracardiac focus, the likelihood ratio was 4.2, RR was 4.8, and PPV was 3.7% (P = .002). Future studies are needed to more precisely address the issue of an isolated echogenic intracardiac focus in a truly low-risk patient (young and with normal triple screen results).

Addendum
After submission of our manuscript, we became aware of an excellent article that also addressed the issue of an isolated echogenic intracardiac focus (57). In this retrospective investigation of 2,412 high-risk pregnancies with proved karyotypes, the authors concluded that an isolated echogenic intracardiac focus carries an RR of 4.1 for aneuploidy.


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  		Association between Echogenic Intracardiac Focus and Trisomy 21
 


   ACKNOWLEDGMENTS
 
We thank the ultrasonographers and laboratory personnel for their assistance with data collection, Aaron Ostrovsky, BA, in particular for his help in compiling the database, and Maureen Michaud, BA, for her help in manuscript preparation.


   FOOTNOTES
 
Abbreviations: PPV = positive predictive value, RR = relative risk

Author contributions: Guarantor of integrity of entire study, T.C.W.; study concepts, T.C.W., D.A.N.; study design, T.C.W., D.A.N.; definition of intellectual content, T.C.W.; literature research, T.C.W.; clinical studies, V.L.S., T.C.W., D.A.N., C.A.K.; data acquisition, E.Y.C., A.M.A., T.C.W., S.B.U.; data analysis, T.C.W.; statistical analysis, T.C.W.; manuscript preparation, T.C.W; manuscript editing, T.C.W., D.A.N.; manuscript review, T.C.W., D.A.N.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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