ECHOGENIC INTRACARDIAC FOCI

AND CHROMOSOMAL ANEUPLOIDY

• An echogenic intracardiac focus has been associated with an increased risk of Down syndrome and trisomy 13 (1), trisomy 18 and monosomy X (2-5).
• Found in 2% of normal fetuses.
• Bromley and co-workers 1995(6).
• Incidence in normal fetuses = 4.8%
• Incidence in Down syndrome = 18%
• Increased risk of Down syndrome = 4-fold.
• Roberts and Genest (1992) (5). Prospective analysis of histological sections of 415 fetuses, found that a discrete central papillary muscle calcification was significantly higher in fetuses with chromosomal aneuploidy (16% of fetuses with trisomy 21 and 39% of fetuses with trisomy 13 versus 2% of control cases).
  At this time it is not certain whether papillary muscle calcification is always evident as an echogenic focus on ultrasound.

Ref	MA (yrs)	Ga (wks)	Location	Other ultrasound findings
7 1 2 6 8 9 7	Not stated 35 24 39 37 >34 >34 >34 Not stated 25 41 20 33 37 39 28 39 36 41 39 24 Not stated Not stated Not stated	Not stated 19 16 20 19 Not stated 14 Not stated Not stated Not stated 18 22 19 18 16 16 18 20 15 16 17 Not stated Not stated Not stated	LV LV LV + RV LV LV LV LV LV LV + RV LV + RV LV LV LV + RV LV Rv LV LV LV LV LV LV LV LV LV	None Pyelectasis Ý Nuchal fold Echogenic lungs Pyelectasis Ý Nuchal fold None None None None Ý Nuchal fold Ý Nuchal fold, ventriculomegaly heart defect, short long bones Ý Nuchal fold, ventriculomegaly clinodactyly, short long bones Ý Nuchal fold, pyelectasis short long bones Ventriculomegaly, echogenic bowel heart defect, short long bones Ý Nuchal fold, echogenic bowel, heart defect, short long bones Ý Nuchal fold Ý Nuchal fold, clinodactyly ventriculomegaly None Echogenic bowel, short long bones Echogenic bowel, short long bones None None Pyelectasis, heart defect

An association between EIF and aneuploidy was first suggested in the early 1990s when calcification of the papillary muscle was noted in:

· 39% of abortuses with trisomy 13,

· 16% of abortuses with trisomy 21,

· 2% of euploid abortuses (11).

· Bromley et al (12) prospectively evaluated 1334 patients referred for amniocentesis and found that 4 (18%) of 22 fetuses with trisomy 21 had EIF, compared with only 62 (4.7%) of 1312 fetuses without trisomy 21.

· Similarly, Manning et al (13) reviewed the ultrasounds of 901 high-risk women who underwent amniocentesis at the time of targeted ultrasound and found that 3 (13%) of 24 fetuses with EIF had Down syndrome, significantly more than fetuses without EIF (14 [2%] of 877 fetuses, P = .009).

· Vibhakar et al (14) confirmed these findings in a retrospective cohort study of 2412 women undergoing amniocentesis, which showed that fetuses with EIF had a relative risk of 3.3 of aneuploidy when compared with fetuses without EIF. Furthermore, in this series the presence of isolated EIF carried a relative risk of 4.1 when compared with those fetuses that sonographically had no other findings associated with aneuploidy.

· Winter et al (15) prospectively evaluated 3303 consecutive fetuses in a high-risk population and determined that EIF was found in 4.6% of normal fetuses and 30% of fetuses with trisomy 21. For a sonographically isolated EIF, the sensitivity, specificity, and positive predictive value were calculated to be 19%, 95%, and 3.7%, respectively, with a relative risk of 4.8.

Although these data suggest an association of EIF with Down syndrome, these studies were all performed in high-risk, selected populations (most of the patients had been referred for amniocentesis), in which amniocentesis is normally recommended even without the presence of EIF.

It is more useful to evaluate the risk of aneuploidy in association with EIF in low-risk (< age 35) populations, particularly when EIF is an isolated finding, because it is in those instances that the finding of EIF can influence recommendations for invasive testing.

There are few studies evaluating EIF in a low-risk population.

· A large, prospective, population-based observational study of 12,373 women identified 267 cases of EIF:

· 72% (193 of 9167) of which were found in women under the age of 35 (16).

· The overall incidence of EIF in this series was 2.2%;

· 2.1% in women less than 35 and 3.4% for fetuses of mothers greater than or equal to 35 years old.

· Isolated EIF was present in 1.6% of women less than 35 and 1.8% of women greater than or equal to 35. Of the 193 cases in low-risk women (< age 35), EIF was an isolated sonographic finding in 149 fetuses (77% of EIF cases in women < age 35). None of the cases of isolated EIF detected on second-trimester ultrasound in women less than 35 was associated with aneuploidy. The authors concluded that EIF as an isolated finding on second-trimester ultrasound in a woman less than age 35 does not change the risk of aneuploidy and does not warrant invasive testing. Other authors have agreed with this appraisal (17).

· Caughey et al (18) created a decision analytic model that compared the standard of second-trimester triple marker screen for Down syndrome with a policy in which amniocentesis with an isolated EIF on ultrasound (in addition to the triple marker screen) is offered to all women in the United States who are less than 35 years of age. The authors calculated that using isolated EIF as a screen results in an additional 118,146 amniocenteses performed annually to diagnose 244 fetuses with Down syndrome, which results in 2.4 procedure-related losses for each additional Down syndrome fetus that was identified.

Echogenic intracardiac foci are not very useful as a marker for aneuploidy primarily because it is detected in only 11% to 30% of Down syndrome fetuses, which explains its low sensitivity (18-21).

Diagnostic performance of echogenic intracardiac foci for Down syndrome
	% Sensitivity	% Specificity	Likelihood ratio
All EIF	26	96	6.2
Isolated EIF	22	96	5.4
Combined EIF	26	96	7
Sotiriadis A, Makrydimas G, Ioannidis PA. Diagnostic performance of intracardiac echogenic foci for Down syndrome: a meta-analysis. Obstet Gynecol 2003;101:1009–1016; .
A recent meta-analysis evaluating the performance of EIF for Down syndrome in 11 studies with a total of 51,831 patients found the overall sensitivity and specificity of EIF for predicting Down syndrome to be only 26% (95% CI 14%, 33%) and 95.8% (95% CI 91%, 98.2%), respectively. The sensitivity drops even further to 22% when EIF is an isolated finding. The authors calculated that, in general, the prior risk of Down syndrome, as calculated by maternal age, history of previous affected pregnancy, and prior screening tests, is increased by a factor of 5.4 when EIF are present, and is reduced by a factor of 0.8 when no foci are detected.

In the absence of aneuploidy, EIF has not been associated with structural cardiac abnormalities (22).

One study suggested that multiple or right-sided foci may have a worse prognosis when compared with single left-sided foci, but others show no such association (23,24).

A recent study found that early ventricular filling and active atrial filling peak velocity ratios were significantly lower in fetuses with EIF, which may indicate cardiac diastolic dysfunction (25). Despite this finding, there does not seem to be any increase in childhood myocardial dysfunction when compared with the general population, although EIF may persist into early childhood (26).

As with any other abnormal finding on ultrasound, the detection of an EIF should prompt a detailed sonographic examination to search for any associated anomalies.

· In the setting of other sonographic abnormalities, or in a high-risk population (women of advanced maternal age, women with a history of a chromosomal abnormality), EIF may carry some clinical significance, and an amniocentesis to rule out aneuploidy should be recommended.

· Data that are available from low-risk populations seem to indicate, however, that isolated EIF is not associated with an increased risk of Down syndrome, or if it is, that risk is much less than the procedure-related loss rates associated with invasive testing. Because there is no association of EIF with structural cardiac disease, further evaluation of EIF is not necessary either prenatally or postnatally.

REFERENCES

1. Brown DL, Roberts DJ, Miller WA. Left ventricular echogenic focus in the fetal heart, pathologic correlation J Ultrasound Med 1994; 13:613-616.
2. Speulveda W, Cullen S, Nicolaidis P et.al. Echogenic foci in the fetal heart: a marker for chromosomal abnormality. Br J Obstet Gynaecol 1995;102:490-492.
3. Twining P. Echogenic foci in the fetal heart: incidence and association with chromosomal disease. Ultrasound Obstet Gynecol 1993;3(Suppl. 2):175.
4. Lehman CD, Nyberg DA, Winter TC et.al. Trisomy 13 syndrome, prenatal US findings in a review of 33 cases Radiology 1995; 194:217-222
5. Roberts DJ, Genest D. Cardiac histologic pathology characteristics of trisomies 13 and 21. Hum Pathol 1992; 23:1130-1140
6. Bromley B, Lieberman E, Laboda LA, Bernacerraf BR. Echogenic intracardiac focus, a sonographic sign for Down syndrome. Obstet Gynecol 1995; 86:998-1001
7. Schechter AG, Fakhry J, Shapiro LR et.al. In utero thickening of the chordae tendinae. A cause of intracardiac echogenic foci. J Ultrasound Med 1987;6:691-695.
8. Simpson JM, Cook A, Sharland G. The significance of echogenic foci in the fetal heart: a prospective study of 228 cases. Ultrasound Obstet Gynecol 1996;8:225-228.
9. Bromley B, Lieberman E, Shipp TD et.al. Significance of echogenic intracardiac intracardiac focus in fetuses at high and low risk for aneuploidy. J Ultrasound Med 1998;17:127-131.
10. 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. Am J Roentgenol 1998;170:1083-1084.
11. Roberts DJ, Genest D. Cardiac histologic pathology characteristic of trisomies 13 and 21. Hum Pathol 1992;23:1130-40
12. Bromley B, Lieberman E, Laboda L, Benacerraf BR. Echogenic intracardiac focus: a sonographic sign for fetal Down syndrome. Obstet Gynecol 1995;86:998-1001.  
13. Manning JE, Ragavendra N, Sayre J, Leifer-Narin SL, Melany ML, Grant EG, 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;170:1083-4.  
14. 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 population. J Ultrasound Med 1999;18:265-8.  
15. Winter TC, Anderson AM, Cheng EY, Komarniski CA, Souter VL, Uhrich SB, et al. Echogenic intracardiac focus in 2nd-trimester fetuses with trisomy 21: usefulness as a US marker. Radiology 2000;216:450-6.  
16. Anderson N, Jyoti R. Relationship of isolated fetal intracardiac echogenic focus to trisomy 21 at the mid-trimester sonogram in women younger than 35 years. Ultrasound Obstet Gynecol 2003;21:354-8.  
17. Achiron R, Lipitz S, Gabbay U, Yagel S. Prenatal ultrasonographic diagnosis of fetal heart echogenic foci: no correlation with Down syndrome. Obstet Gynecol 1997;89:
18. Caughey AB, Lyell DJ, Filly RA, Washington AE, Norton ME. The impact of the use of the isolated echogenic intracardiac focus as a screen for Down syndrome in women under the age of 35 years. Am J Obstet Gynecol 2001;185:1021-7.  
19. Shipp TD, Benacerraf BR. Second trimester ultrasound screening for chromosomal abnormalities. Prenat Diagn 2002;22:296-307.  
20. Sotiriadis A, Makrydimas G, Ioannidis PA. Diagnostic performance of intracardiac echogenic foci for Down syndrome: a meta-analysis. Obstet Gynecol 2003;101:1009-16.  
21. Smith-Bindman R, Hosmer W, Feldstein VA, Deeks JJ, Goldberg JD. Second-trimester ultrasound to detect fetuses with Down syndrome: a meta-analysis. JAMA 2001;285:1044-55
22. Wolman I, Jaffa A, Geva E, Diamant S, Strauss S, Lessing JB, et al. Intracardiac echogenic focus: no apparent association with structural cardiac abnormality. Fetal Diagn Ther 2000;15:216-8.  
23. Bronshtein M, Jakobi P, Ofir C. Multiple fetal intracardiac echogenic foci: not always a benign sonographic finding. Prenat Diagn 1996;16:131-5.  
24. Petrikovsky B, Challenger M, Gross B. Unusual appearances of echogenic foci within the fetal heart: are they benign? Ultrasound Obstet Gynecol 1996;8:229-31.  
25. Degani S, Leibovitz Z, Shapiro I, Gonen R, Ohel G. Cardiac function in fetuses with intracardiac echogenic foci. Ultrasound Obstet Gynecol 2001;18:131
26. Wax JR, Donnelly J, Carpenter M, Chard R, Pinette MG, Blackstone J, et al. Childhood cardiac function after prenatal diagnosis of intracardiac echogenic foci. J Ultrasound Med 2003;22:783-7.