- Email: [email protected]
Association between increased nuchal translucency and second trimester cardiac echogenic foci
Association Between Increased Nuchal Translucency and Second Trimester Cardiac Echogenic Foci Federico Prefumo, MD, Francesca Presti, MD, Baskaran Thilaganathan, MD, MRCOG, and Julene S. Carvalho, MD, FRCPCH OBJECTIVE: To test the hypothesis that increased first trimester nuchal translucency is associated with isolated cardiac foci in the second trimester. METHODS: We identified all pregnancies delivered between January 1997 and June 2000. We included 7686 normal singleton fetuses who had a nuchal translucency scan and either a subsequent normal anomaly scan at 18 –23 weeks’ gestation (n ⴝ 7447) or isolated cardiac foci (n ⴝ 239). Fetuses were divided into two groups: normal (95th percentile or less) and increased (greater than 95th percentile) nuchal translucency. RESULTS: The prevalence of cardiac echogenic foci in fetuses with normal nuchal translucency was 218 of 7427 (2.9%; 95% confidence interval [CI] 2.6, 3.3%), whereas 21 of 259 fetuses (8.1%; 95% CI 5.1, 12.1%) with increased nuchal translucency were subsequently found to have cardiac foci. The adjusted odds ratio for cardiac echogenic foci in cases of increased nuchal translucency was 2.92 (95% CI 1.83, 4.66). CONCLUSION: An association exists between first trimester nuchal translucency and second trimester cardiac echogenic foci. Risk calculation algorithms for trisomy 21 based on nuchal translucency thickness should not use cardiac foci as an independent marker. (Obstet Gynecol 2003; 101:899 –904. © 2003 by The American College of Obstetricians and Gynecologists.)
Nuchal translucency measurement at 11–14 weeks’ gestation has been demonstrated to be an effective screening test for Down syndrome, either alone1 or in combination with maternal serum pregnancy–associated plasma protein-A and the free  subunit of human chorionic gonadotropin.2 As a result, nuchal translucency screening is being offered to a significant proportion of the pregnant From the Fetal Medicine Unit, Department of Obstetrics and Gynecology, St. George’s Hospital Medical School; and Brompton Fetal Cardiology, Royal Brompton Hospital, London, United Kingdom. This research has been partially supported by a Marie Curie Fellowship of the European Community program Quality of Life under contract number QLGA-CT2000-52145. JSC is partially funded by the Hyman Marks Research Fund, Royal Brompton Hospital.
population in the United Kingdom and in Europe. Additionally, increased nuchal translucency has also been associated with a higher prevalence of major congenital heart defects in the fetus.3– 6 Intracardiac echogenic foci are small echoes seen within the cardiac ventricles on prenatal ultrasound. They are characteristically related to the papillary muscle of the mitral valve but can also be seen in the right ventricle. Their echogenicity is similar to the surrounding bone and, therefore, they are hyperechoic compared with the remainder of the myocardium. The prevalence of intracardiac echogenic foci at the anomaly scan varies from 0.5%7 to 20%.8 They are not known to be of pathologic significance, but their significance as a marker for chromosomal abnormality, in particular trisomy 21, is much debated. Some studies have indicated that, if found in isolation, they are not associated with an increased risk of aneuploidy,9 –13 whereas others have reported on a significantly increased risk.14 –17 When observed in an apparently normal four-chamber view, cardiac echogenic foci do not seem to be associated with structural cardiac abnormalities.18,19 Increased nuchal translucency measurement is a transient ultrasonographic finding whose pathogenesis is unknown. It is seen between 11 and 14 weeks’ gestation but often disappears after this period. Echogenic focus in the heart is also a usually transient ultrasonographic finding for which the underlying etiology is unknown. The purpose of this study was to investigate the possible relationship between first trimester nuchal translucency measurements and the presence or absence of isolated intracardiac echogenic foci in the second trimester of pregnancy. MATERIALS AND METHODS Patients who received all their prenatal care and delivered at our hospital between January 1997 and June 2000 were identified from our computerized clinical database. We included in our study all singleton fetuses who had both a nuchal translucency scan and a subsequent anom-
VOL. 101, NO. 5, PART 1, MAY 2003 © 2003 by The American College of Obstetricians and Gynecologists. Published by Elsevier.
0029-7844/03/$30.00 doi:10.1016/S0029-7844(02)03128-9
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aly scan at 18 –23 weeks’ gestation, or the diagnosis of isolated intracardiac echogenic foci at the second trimester scan. Pregnancies referred from other hospitals were excluded to eliminate bias, as were any pregnancies diagnosed with aneuploidy or abnormalities other than isolated intracardiac echogenic foci. Fetuses who had an incomplete structural assessment between 18 and 23 weeks owing to technical reasons, and whose normality was confirmed later at ultrasound, were also excluded. All fetuses had routine first trimester nuchal translucency scans and second trimester anomaly scans performed by experienced ultrasonographers or obstetricians, using standard obstetric mode ultrasound machine settings. Nuchal translucency thickness was measured in viable pregnancies with a crown–rump length between 38 and 84 mm, employing a standardized technique.1 During the study period, most fetuses with intracardiac echogenic foci were referred for detailed echocardiography as part of our risk assessment for chromosomal abnormalities in individual pregnancies. The anatomy of the fetal heart was assessed using a sequential segmental approach,20 complemented by the use of color flow mapping, and pulsed-wave Doppler when indicated. All scans were carried out with either a 3–5-MHz or a 5–7-MHz curvilinear probe, using different ultrasound equipment (ATL, Bothell, WA; Acuson, Mountain View, CA; General Electric, Waukesha, WI; Diasonics, Santa Clara, CA). Hospital records were reviewed to determine delivery outcomes for each subject. Results were also crossmatched with the registry of the Regional Genetics Service, covering genetic and cytogenetic testing for the whole region. The neonatal and pediatric surgery unit of our institution regularly notified all cases of abnormalities diagnosed postnatally. All cases of major congenital heart disease diagnosed in our institution are referred to a single cardiothoracic center, whose database was also reviewed to identify patients from our unit undergoing long-term follow-up, interventional cardiac catheterization, or surgery. The study was approved by the local institutional review boards. During the study period, all cases of trisomy 13 and 18 were diagnosed prenatally, either because of an increased nuchal translucency or because of abnormal findings at the anomaly scan. Fifteen cases of trisomy 21 were identified and confirmed antenatally by a combination of maternal age and nuchal translucency in the first trimester of pregnancy. After chorionic villus sampling, all pregnancies either miscarried spontaneously or were terminated. There were a total of six trisomy 21 deliveries at term. Four of the latter were identified as high risk antenatally: two with increased nuchal translucency and two with ultrasound abnormalities on second trimester
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ultrasound. The prevalence of major congenital heart disease in our population was estimated at 4.3 per 1000, with an overall antenatal detection rate of 75% during the study period.21 In the cases with congenitally abnormal hearts for which nuchal translucency was assessed in early pregnancy, an increased nuchal measurement was present only in 15% of the fetuses.6 A total of 8835 fetuses were identified as having received prenatal care at our institution, including both a first trimester nuchal translucency scan and a subsequent anomaly scan at 18 –23 weeks’ gestation. In 356 fetuses, the anomaly scan was incomplete owing to technical reasons. Another 242 fetuses were lost at follow-up because they did not deliver at our hospital, and 24 suffered intrauterine death in the absence of structural or chromosomal abnormalities. Some abnormal finding, including structural and chromosomal abnormalities and any sonographic soft marker except for cardiac echogenic foci, was observed in 288 fetuses, either prenatally on ultrasound or postnatally. This group included 30 fetuses with cardiac echogenic foci and other soft markers (choroid plexus cysts, mild renal pelvis dilatation, hyperechogenic bowel) and 15 fetuses with cardiac echogenic foci and structural abnormalities (one talipes, 11 cardiac abnormalities, one diaphragmatic hernia, and one multicystic dysplastic kidney). The two cases with echogenic foci and abnormal karyotype (one with trisomy 21 and one with mosaic trisomy 20) both showed associated ultrasound findings. In the remaining 7686 fetuses with a normal outcome, the anomaly scan was entirely normal in 7447 fetuses, whereas 239 fetuses showed an isolated intracardiac echogenic focus. We calculated regression equations for the 5th, 50th, and 95th percentile of nuchal translucency measurements with the method of scaled absolute residuals22 from 11,847 singleton pregnancies screened at our institution between November 1996 and August 2000. Briefly, after calculating a regression curve for the mean, the standard deviation (SD) of the measurements was estimated from the residuals (difference between the measurements and the estimated curve for the mean) with the sign removed and multiplied by 1.25.22 Centile curves were calculated using the formula centile ⫽ mean ⫹ K ⫻ SD, where K is the corresponding centile of the standard Gaussian distribution. The prevalence of second trimester echogenic foci in cases showing a nuchal translucency measurement at the 95th centile or less or greater than the 95th centile was calculated, based on the 95th percentile regression equation. Confidence intervals (CIs) for this prevalence were calculated using the exact binomial method.23 Odds ratios and their 95% CIs were calculated as previously described.24 To take into account the effect of other predictor variables on the
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Table 1. Demographic Characteristics in 7686 Fetuses With an Ascertained Normal Outcome Who Underwent First Trimester Nuchal Translucency Screening Cardiac echogenic foci
Maternal age (y) Mean parity (range) First trimester bleeding Gestational age at first scan (wk) Gestational age at second scan (wk) Nuchal translucency ⬎ 95th centile
Present (n ⫽ 239)
Absent (n ⫽ 7447)
P
30.0 ⫾ 5.5 0.7 (0–6) 24 (10) 12.5 ⫾ 0.7 20.7 ⫾ 1.0 21 (8.8)
30.3 ⫾ 5.4 0.7 (0–24) 892 (12) 12.4 ⫾ 0.7 20.7 ⫾ 0.93 238 (3.2)
.50* .75† .36‡ .07* .78* ⬍.001‡
Data presented as mean ⫾ standard deviation or n (%). The second trimester ultrasound scan was either completely normal or showed isolated intracardiac echogenic foci as an isolated finding. * Student t test. † Mann-Whitney test. ‡ 2 test.
prevalence of cardiac echogenic foci, a logistic regression model was applied to calculate adjusted odds ratios and their 95% CIs.25 Statistical calculations were performed using SPSS for Windows 10.0.05 software (SPSS Inc., Chicago, IL).
RESULTS A total of 7686 fetuses with nuchal translucency measurement were analyzed. The anomaly scan was entirely normal in 7447 fetuses, whereas 239 fetuses showed an isolated intracardiac echogenic focus. The demographic characteristics of the two groups are compared in Table 1. Based on the crown–rump length–specific regression equation for the 95th percentile of nuchal translucency at our institution, all fetuses were divided in two groups: those with a normal nuchal translucency (95th percentile or less) and those with an increased nuchal translucency (greater than 95th percentile). Of 7427 fetuses with a normal nuchal translucency, 218 were subsequently found to have cardiac echogenic foci (prevalence 2.9%; 95% CI 2.6%, 3.3%) whereas 21 of 259 with an increased nuchal translucency showed echogenic foci at the time of the anomaly scan (prevalence 8.1%; 95% CI 5.1%, 12.1%). Fetuses with increased nuchal translucency were 2.92 times (95% CI 1.83, 4.65) more likely to have cardiac echogenic foci in the second trimester compared with those with a normal nuchal translucency. A multivariable logistic regression model was calculated for the prediction of cardiac echogenic foci, using maternal age, gestational age at the first scan, parity, presence or absence of first trimester bleeding, and presence or absence of increased nuchal translucency as variables. The adjusted odds ratios derived from the analysis are shown in Table 2.
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DISCUSSION Based on data from a large, unselected, pregnant population, it was possible to demonstrate a significant association between raised first trimester nuchal translucency measurements and an increased prevalence of isolated intracardiac echogenic foci in the second trimester in otherwise normal fetuses. Because this was a retrospective study and the operators performing the second trimester scan were not blinded to the results of first trimester nuchal translucency measurement, there is a potential bias in the reporting of intracardiac echogenic foci (ie, in cases with an increased nuchal translucency the cardiac examination may have been more detailed owing to the known increased risk of cardiac abnormalities), leading to a higher rate of identification of echogenic foci. Only a prospective, blinded trial could exclude this bias. However, we think that this had only a minor effect in our study. During the period considered,
Table 2. Adjusted Odds Ratios From the Logistic Regression for Predicting Second Trimester Cardiac Echogenic Foci Odds ratio
P
95% confidence interval
1.01 0.99 0.83
.40 .88 .38
0.99, 1.04 0.87, 1.12 0.54, 1.27
0.83
.07
0.67, 1.01
1.04
.62
0.90, 1.19
2.92
⬍.001
1.83, 4.66
Maternal age Parity First trimester bleeding Gestational age at first scan Gestational age at second scan Nuchal translucency ⬎ 95th centile
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an active program of training and auditing of the operators was implemented, including the optimization of ultrasound machine settings to obtain satisfactory cardiac images and the use of a checklist for detailed assessment of the four-chamber and outlet views.21 The presence or absence of intracardiac echogenic foci was one of the items in the checklist. As an effect, the presence of echogenic foci was the most common reason for referral for fetal echocardiography during the study period (26% of cardiac referrals), demonstrating the high reporting rate for this finding in the population examined. The limited understanding of the mechanisms underlying increased nuchal translucency and cardiac echogenic foci makes the interpretation of the association between the two findings difficult. Although direct evidence of abnormal myocardial function has not been demonstrated in the first-trimester fetus with increased nuchal translucency, a significant proportion of fetuses with chromosomal or cardiac abnormalities exhibit absent or reversed flow in the ductus venosus during atrial contraction.26 –29 The latter is indirect evidence supporting the hypothesis of disturbed cardiac function in the etiology of increased nuchal translucency.4,30 Hence, in fetuses with congenital heart defects, thoracic tumors, and skeletal dysplasias affecting the thorax, one could postulate impaired cardiac function as the etiologic mechanism for the development of increased nuchal translucency. However, there is no satisfactory explanation for the pathogenesis of increased nuchal translucency when it occurs in fetuses subsequently shown to develop normally without a chromosomal or structural defect. In contrast to the findings with nuchal translucency, few articles have reported histologic findings in fetal hearts diagnosed with echogenic foci.31,32 These describe focal intramyocardial calcifications in the papillary muscles surrounded by fibrotic tissue. In the series by Tennstedt et al32 no myocyte necrosis, inflammatory infiltrates, or evidence of bleeding were observed to provide an explanation for the origin of the calcifications. In addition, the authors could not find any differences between fetuses with normal and abnormal karyotype. Only one article has addressed cardiac function in fetuses with echogenic foci.33 Degani and colleagues33 investigated diastolic function in 48 second-trimester fetuses with left ventricular echogenic foci by means of early ventricular or active atrial filling peak velocity ratios at Doppler fetal echocardiography. The authors showed lower ratios for the mitral as well as the tricuspid valve, suggesting that fetuses with echogenic foci may have some degree of diastolic dysfunction affecting both
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ventricles. However, the clinical significance of these observations remains to be determined. The finding of this study of an association between increased nuchal translucency and intracardiac echogenic foci raises the possibility that a common causal mechanism may underlie the two conditions. From animal studies, it is known that myocardial structure and function change during fetal development and that fetal myocardium is less compliant than in the adult.34 In humans, by 10 weeks’ gestation, significant changes in myocardial function have already taken place, as shown by a change from a monophasic (A wave) to a biphasic (A and E waves) Doppler pattern across the atrioventricular valves.35 Leiva et al have also shown that fetuses who showed a delay in this change during cardiac development had a worse outcome.35 It is therefore possible that if normal myocardial development and the process of myocardial maturation were delayed, persistence of a less compliant myocardium beyond 10 weeks may underlie the development of an increased nuchal translucency because of poorer cardiac diastolic function. Suboptimal cardiac function in the first trimester may lead not only to increased nuchal translucency, but also to islands of myocardial hypoxia ultimately leading to microcalcifications documented in association with echogenic foci. The effect of such an insult in the first trimester may still be detectable in the second trimester as intracardiac echogenic foci or as a disturbance of diastolic function.33 Further studies are necessary to confirm or refute this possibility. From the clinical point of view, the demonstration of an association between increased nuchal translucency measurements in the first trimester and the presence of second trimester isolated cardiac echogenic foci has relevant implications. First, if the association is confirmed, then nuchal translucency measurements and isolated echogenic foci cannot be used as independent risk factors for aneuploidy. Moreover, raised nuchal translucency values have mainly been reported to be associated with conditions implying a severe or guarded prognosis, such as chromosomal abnormalities, structural defects, or a series of genetic syndromes.36 However, previously published data suggest that a substantial proportion of fetuses with an abnormally increased nuchal translucency are born alive and have a normal postnatal development.5,37–39 This article provides a description of the association between increased nuchal translucency measurements and an apparently benign condition— cardiac echogenic foci. Delayed myocardial maturation could account for both findings. Should this prove to be correct, then a plausible explanation for the increase of nuchal translucency in normal fetuses would be available.
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REFERENCES 1. Snijders RJM, Noble P, Sebire N, Souka A, Nicolaides KH. UK multicentre project on assessment of risk of trisomy 21 by maternal age and fetal nuchal-translucency thickness at 10 –14 weeks of gestation. Lancet 1998;351:343–6. 2. De Biasio P, Siccardi M, Volpe G, Famularo L, Santi F, Canini S. First-trimester screening for Down syndrome using nuchal translucency measurement with free -hCG and PAPP-A between 10 and 13 weeks of pregnancy: the combined test. Prenat Diagn 1999;19:360–3. 3. Hyett J, Moscoso G, Papapanagiotou G, Perdu M, Nicolaides KH. Abnormalities of the heart and great arteries in chromosomally normal fetuses with increased nuchal translucency thickness at 11–13 weeks of gestation. Ultrasound Obstet Gynecol 1996;7:245–50. 4. Carvalho JS. Nuchal translucency, ductus venosus and congenital heart disease: An important association, a cautious analysis. Ultrasound Obstet Gynecol 1999;14:302–6. 5. Michailidis GD, Economides DL. Nuchal translucency measurement and pregnancy outcome in karyotypically normal fetuses. Ultrasound Obstet Gynecol 2001;17: 102–5. 6. Mavrides E, Cobian-Sanchez F, Tekay A, Moscoso G, Campbell S, Thilaganathan B, et al. Limitations of using first-trimester nuchal translucency measurement in routine screening for major congenital heart defects. Ultrasound Obstet Gynecol 2001;17:106–10. 7. How HY, Villafane J, Parihus RR, Spinnato JA. Small hyperechoic foci of the fetal cardiac ventricle: A benign sonographic finding? Ultrasound Obstet Gynecol 1994;4: 205–7. 8. Levy DW, Mintz MC. The left ventricular echogenic focus: A normal finding. AJR Am J Roentgenol 1988;150: 85–6. 9. Dildy GA, Judd VE, Clark SL. Prospective evaluation of antenatal incidence and postnatal significance of the fetal echogenic cardiac focus: A case-control study. Am J Obstet Gynecol 1996;175:1008–12. 10. Merati R, Lovotti M, Norchi S, Teatini A, Tenore AC, Belloni C. Prevalence of fetal left ventricular hyperechogenic foci in a low risk population. Br J Obstet Gynaecol 1996;103:1102–4. 11. Achiron R, Lipitz S, Gabbay U, Yagel S. Prenatal ultrasonographic diagnosis of fetal heart echogenic foci: No correlation with Down syndrome. Obstet Gynecol 1997; 89:945–8. 12. Thilaganathan B, Olawaiye A, Sairam S, Harrington K. Isolated fetal echogenic foci or golf balls: Is karyotyping for Down’s syndrome indicated? Br J Obstet Gynaecol 1999; 106:1294–7. 13. Prefumo F, Presti F, Mavrides E, Sanusi AF, Bland JM, Campbell S, et al. Isolated echogenic foci in the fetal heart: Do they increase the risk of trisomy 21 in a population previously screened by nuchal translucency? Ultrasound Obstet Gynecol 2001;18:126–30.
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14. 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;8:225–8. 15. 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. 16. Jaffe R, Cherot E, Allen T, Glantz JC. Significance of echogenic foci in the left ventricle of the fetal heart in a low-risk population. Fetal Diagn Ther 1999;14:345–7. 17. Huggon IC, Cook AC, Simpson JM, Smeeton NC, Sharland GK. Isolated echogenic foci in the fetal heart as a marker of chromosomal abnormality. Ultrasound Obstet Gynecol 2001;17:11–6. 18. 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. 19. Wax JR, Mather J, Steinfeld JD, Ingardia CJ. Fetal intracardiac echogenic foci: Current understanding and clinical significance. Obstet Gynecol Surv 2000;55:303–11. 20. Shinebourne EA, Macartney FJ, Anderson RH. Sequential chamber localization—logical approach to diagnosis in congenital heart disease. Br Heart J 1976;38:327–40. 21. Carvalho JS, Mavrides E, Shinebourne EA, Campbell S, Thilaganathan B. Improving the effectiveness of routine prenatal screening for major congenital heart defects. Heart 2002;88:387–91. 22. Royston P, Wright EM. How to construct ‘normal ranges’ for fetal variables. Ultrasound Obstet Gynecol 1998;11: 30–8. 23. Pearson EG, Hartley HO. Biometrika tables for statisticians, volume 1, 3rd ed. Cambridge, United Kingdom: Cambridge University Press, 1970. 24. Bland M. An introduction to medical statistics. Oxford, United Kingdom: Oxford University Press, 2000:240–3. 25. Bland M. An introduction to medical statistics. Oxford, United Kingdom: Oxford University Press, 2000:321–3. 26. Matias A, Gomes C, Flack N, Montenegro N, Nicolaides KH. Screening for chromosomal abnormalities at 10 –14 weeks: The role of ductus venosus blood flow. Ultrasound Obstet Gynecol 1998;12:380–4. 27. Borrell A, Antolin E, Costa D, Farre MT, Martinez JM, Fortuny A. Abnormal ductus venosus flow in trisomy 21 fetuses during early pregnancy. Am J Obstet Gynecol 1998;179:1612–7. 28. Mavrides E, Sairam S, Hollis B, Thilaganathan B. Screening for aneuploidy in the first trimester by assessment of blood flow in the ductus venosus. Br J Obstet Gynaecol 2002;109:1015–9. 29. Bilardo CM, Mu¨ller MA, Zikulnig L, Schipper M, Hecher K. Ductus venosus studies in fetuses at high risk for chromosomal or heart abnormalities: Relationship with
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30.
31.
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35.
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nuchal translucency measurement and fetal outcome. Ultrasound Obstet Gynecol 2001;17:288–94. Montenegro N, Matias A, Areias JC, Castedo S, Barros H. Increased fetal nuchal translucency: Possible involvement of early cardiac failure. Ultrasound Obstet Gynecol 1997; 10:265–8. Brown DL, Roberts DJ, Miller WA. Left ventricular echogenic focus in the fetal heart: Pathologic correlation. J Ultrasound Med 1994;13:613–6. Tennstedt C, Chaoui R, Vogel M, Goldner B, Dietel M. Pathologic correlation of sonographic echogenic foci in the fetal heart. Prenat Diagn 2000;20:287–92. Degani S, Leibovitz Z, Shapiro I, Gonen R, Ohel G. Cardiac function in fetuses with intracardiac echogenic foci. Ultrasound Obstet Gynecol 2001;18:131–4. Friedman WF. The intrinsic physiologic properties of the developing heart. Prog Cardiovasc Dis 1972;15: 87–111. Leiva MC, Tolosa JE, Binotto CN, Weiner S, Huppert L, Denis AL, et al. Fetal cardiac development and hemodynamics in the first trimester. Ultrasound Obstet Gynecol 1999;14:169–74.
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36. Bilardo CM. Increased nuchal translucency and normal karyotype: Coping with uncertainty. Ultrasound Obstet Gynecol 2001;17:99–101. 37. Bilardo CM, Pajkrt E, de Graaf I, Mol BW, Bleker OP. Outcome of fetuses with enlarged nuchal translucency and normal karyotype. Ultrasound Obstet Gynecol 1998;11: 401–6. 38. Hiippala A, Eronen M, Taipale P, Salonen R, Hiilesmaa V. Fetal nuchal translucency and normal chromosomes: A long-term follow-up study. Ultrasound Obstet Gynecol 2001;18:18–22. 39. Souka AP, Krampl E, Bakalis S, Heath V, Nicolaides KH. Outcome of pregnancy in chromosomally normal fetuses with increased nuchal translucency in the first trimester. Ultrasound Obstet Gynecol 2001;18:9–17. Address reprint requests to: Julene S. Carvalho, MD, FRCPCH, Royal Brompton Hospital, Sydney Street, London SW3 6NP, United Kingdom; E-mail: j.carvalho@rbh. nthames.nhs.uk. Received August 14, 2002. Received in revised form October 4, 2002. Accepted November 7, 2002.
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Nuchal translucency measurement at 11–14 weeks’ gestation has been demonstrated to be an effective screening test for Down syndrome, either alone1 or in combination with maternal serum pregnancy–associated plasma protein-A and the free  subunit of human chorionic gonadotropin.2 As a result, nuchal translucency screening is being offered to a significant proportion of the pregnant From the Fetal Medicine Unit, Department of Obstetrics and Gynecology, St. George’s Hospital Medical School; and Brompton Fetal Cardiology, Royal Brompton Hospital, London, United Kingdom. This research has been partially supported by a Marie Curie Fellowship of the European Community program Quality of Life under contract number QLGA-CT2000-52145. JSC is partially funded by the Hyman Marks Research Fund, Royal Brompton Hospital.
population in the United Kingdom and in Europe. Additionally, increased nuchal translucency has also been associated with a higher prevalence of major congenital heart defects in the fetus.3– 6 Intracardiac echogenic foci are small echoes seen within the cardiac ventricles on prenatal ultrasound. They are characteristically related to the papillary muscle of the mitral valve but can also be seen in the right ventricle. Their echogenicity is similar to the surrounding bone and, therefore, they are hyperechoic compared with the remainder of the myocardium. The prevalence of intracardiac echogenic foci at the anomaly scan varies from 0.5%7 to 20%.8 They are not known to be of pathologic significance, but their significance as a marker for chromosomal abnormality, in particular trisomy 21, is much debated. Some studies have indicated that, if found in isolation, they are not associated with an increased risk of aneuploidy,9 –13 whereas others have reported on a significantly increased risk.14 –17 When observed in an apparently normal four-chamber view, cardiac echogenic foci do not seem to be associated with structural cardiac abnormalities.18,19 Increased nuchal translucency measurement is a transient ultrasonographic finding whose pathogenesis is unknown. It is seen between 11 and 14 weeks’ gestation but often disappears after this period. Echogenic focus in the heart is also a usually transient ultrasonographic finding for which the underlying etiology is unknown. The purpose of this study was to investigate the possible relationship between first trimester nuchal translucency measurements and the presence or absence of isolated intracardiac echogenic foci in the second trimester of pregnancy. MATERIALS AND METHODS Patients who received all their prenatal care and delivered at our hospital between January 1997 and June 2000 were identified from our computerized clinical database. We included in our study all singleton fetuses who had both a nuchal translucency scan and a subsequent anom-
VOL. 101, NO. 5, PART 1, MAY 2003 © 2003 by The American College of Obstetricians and Gynecologists. Published by Elsevier.
0029-7844/03/$30.00 doi:10.1016/S0029-7844(02)03128-9
899
aly scan at 18 –23 weeks’ gestation, or the diagnosis of isolated intracardiac echogenic foci at the second trimester scan. Pregnancies referred from other hospitals were excluded to eliminate bias, as were any pregnancies diagnosed with aneuploidy or abnormalities other than isolated intracardiac echogenic foci. Fetuses who had an incomplete structural assessment between 18 and 23 weeks owing to technical reasons, and whose normality was confirmed later at ultrasound, were also excluded. All fetuses had routine first trimester nuchal translucency scans and second trimester anomaly scans performed by experienced ultrasonographers or obstetricians, using standard obstetric mode ultrasound machine settings. Nuchal translucency thickness was measured in viable pregnancies with a crown–rump length between 38 and 84 mm, employing a standardized technique.1 During the study period, most fetuses with intracardiac echogenic foci were referred for detailed echocardiography as part of our risk assessment for chromosomal abnormalities in individual pregnancies. The anatomy of the fetal heart was assessed using a sequential segmental approach,20 complemented by the use of color flow mapping, and pulsed-wave Doppler when indicated. All scans were carried out with either a 3–5-MHz or a 5–7-MHz curvilinear probe, using different ultrasound equipment (ATL, Bothell, WA; Acuson, Mountain View, CA; General Electric, Waukesha, WI; Diasonics, Santa Clara, CA). Hospital records were reviewed to determine delivery outcomes for each subject. Results were also crossmatched with the registry of the Regional Genetics Service, covering genetic and cytogenetic testing for the whole region. The neonatal and pediatric surgery unit of our institution regularly notified all cases of abnormalities diagnosed postnatally. All cases of major congenital heart disease diagnosed in our institution are referred to a single cardiothoracic center, whose database was also reviewed to identify patients from our unit undergoing long-term follow-up, interventional cardiac catheterization, or surgery. The study was approved by the local institutional review boards. During the study period, all cases of trisomy 13 and 18 were diagnosed prenatally, either because of an increased nuchal translucency or because of abnormal findings at the anomaly scan. Fifteen cases of trisomy 21 were identified and confirmed antenatally by a combination of maternal age and nuchal translucency in the first trimester of pregnancy. After chorionic villus sampling, all pregnancies either miscarried spontaneously or were terminated. There were a total of six trisomy 21 deliveries at term. Four of the latter were identified as high risk antenatally: two with increased nuchal translucency and two with ultrasound abnormalities on second trimester
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ultrasound. The prevalence of major congenital heart disease in our population was estimated at 4.3 per 1000, with an overall antenatal detection rate of 75% during the study period.21 In the cases with congenitally abnormal hearts for which nuchal translucency was assessed in early pregnancy, an increased nuchal measurement was present only in 15% of the fetuses.6 A total of 8835 fetuses were identified as having received prenatal care at our institution, including both a first trimester nuchal translucency scan and a subsequent anomaly scan at 18 –23 weeks’ gestation. In 356 fetuses, the anomaly scan was incomplete owing to technical reasons. Another 242 fetuses were lost at follow-up because they did not deliver at our hospital, and 24 suffered intrauterine death in the absence of structural or chromosomal abnormalities. Some abnormal finding, including structural and chromosomal abnormalities and any sonographic soft marker except for cardiac echogenic foci, was observed in 288 fetuses, either prenatally on ultrasound or postnatally. This group included 30 fetuses with cardiac echogenic foci and other soft markers (choroid plexus cysts, mild renal pelvis dilatation, hyperechogenic bowel) and 15 fetuses with cardiac echogenic foci and structural abnormalities (one talipes, 11 cardiac abnormalities, one diaphragmatic hernia, and one multicystic dysplastic kidney). The two cases with echogenic foci and abnormal karyotype (one with trisomy 21 and one with mosaic trisomy 20) both showed associated ultrasound findings. In the remaining 7686 fetuses with a normal outcome, the anomaly scan was entirely normal in 7447 fetuses, whereas 239 fetuses showed an isolated intracardiac echogenic focus. We calculated regression equations for the 5th, 50th, and 95th percentile of nuchal translucency measurements with the method of scaled absolute residuals22 from 11,847 singleton pregnancies screened at our institution between November 1996 and August 2000. Briefly, after calculating a regression curve for the mean, the standard deviation (SD) of the measurements was estimated from the residuals (difference between the measurements and the estimated curve for the mean) with the sign removed and multiplied by 1.25.22 Centile curves were calculated using the formula centile ⫽ mean ⫹ K ⫻ SD, where K is the corresponding centile of the standard Gaussian distribution. The prevalence of second trimester echogenic foci in cases showing a nuchal translucency measurement at the 95th centile or less or greater than the 95th centile was calculated, based on the 95th percentile regression equation. Confidence intervals (CIs) for this prevalence were calculated using the exact binomial method.23 Odds ratios and their 95% CIs were calculated as previously described.24 To take into account the effect of other predictor variables on the
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Table 1. Demographic Characteristics in 7686 Fetuses With an Ascertained Normal Outcome Who Underwent First Trimester Nuchal Translucency Screening Cardiac echogenic foci
Maternal age (y) Mean parity (range) First trimester bleeding Gestational age at first scan (wk) Gestational age at second scan (wk) Nuchal translucency ⬎ 95th centile
Present (n ⫽ 239)
Absent (n ⫽ 7447)
P
30.0 ⫾ 5.5 0.7 (0–6) 24 (10) 12.5 ⫾ 0.7 20.7 ⫾ 1.0 21 (8.8)
30.3 ⫾ 5.4 0.7 (0–24) 892 (12) 12.4 ⫾ 0.7 20.7 ⫾ 0.93 238 (3.2)
.50* .75† .36‡ .07* .78* ⬍.001‡
Data presented as mean ⫾ standard deviation or n (%). The second trimester ultrasound scan was either completely normal or showed isolated intracardiac echogenic foci as an isolated finding. * Student t test. † Mann-Whitney test. ‡ 2 test.
prevalence of cardiac echogenic foci, a logistic regression model was applied to calculate adjusted odds ratios and their 95% CIs.25 Statistical calculations were performed using SPSS for Windows 10.0.05 software (SPSS Inc., Chicago, IL).
RESULTS A total of 7686 fetuses with nuchal translucency measurement were analyzed. The anomaly scan was entirely normal in 7447 fetuses, whereas 239 fetuses showed an isolated intracardiac echogenic focus. The demographic characteristics of the two groups are compared in Table 1. Based on the crown–rump length–specific regression equation for the 95th percentile of nuchal translucency at our institution, all fetuses were divided in two groups: those with a normal nuchal translucency (95th percentile or less) and those with an increased nuchal translucency (greater than 95th percentile). Of 7427 fetuses with a normal nuchal translucency, 218 were subsequently found to have cardiac echogenic foci (prevalence 2.9%; 95% CI 2.6%, 3.3%) whereas 21 of 259 with an increased nuchal translucency showed echogenic foci at the time of the anomaly scan (prevalence 8.1%; 95% CI 5.1%, 12.1%). Fetuses with increased nuchal translucency were 2.92 times (95% CI 1.83, 4.65) more likely to have cardiac echogenic foci in the second trimester compared with those with a normal nuchal translucency. A multivariable logistic regression model was calculated for the prediction of cardiac echogenic foci, using maternal age, gestational age at the first scan, parity, presence or absence of first trimester bleeding, and presence or absence of increased nuchal translucency as variables. The adjusted odds ratios derived from the analysis are shown in Table 2.
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DISCUSSION Based on data from a large, unselected, pregnant population, it was possible to demonstrate a significant association between raised first trimester nuchal translucency measurements and an increased prevalence of isolated intracardiac echogenic foci in the second trimester in otherwise normal fetuses. Because this was a retrospective study and the operators performing the second trimester scan were not blinded to the results of first trimester nuchal translucency measurement, there is a potential bias in the reporting of intracardiac echogenic foci (ie, in cases with an increased nuchal translucency the cardiac examination may have been more detailed owing to the known increased risk of cardiac abnormalities), leading to a higher rate of identification of echogenic foci. Only a prospective, blinded trial could exclude this bias. However, we think that this had only a minor effect in our study. During the period considered,
Table 2. Adjusted Odds Ratios From the Logistic Regression for Predicting Second Trimester Cardiac Echogenic Foci Odds ratio
P
95% confidence interval
1.01 0.99 0.83
.40 .88 .38
0.99, 1.04 0.87, 1.12 0.54, 1.27
0.83
.07
0.67, 1.01
1.04
.62
0.90, 1.19
2.92
⬍.001
1.83, 4.66
Maternal age Parity First trimester bleeding Gestational age at first scan Gestational age at second scan Nuchal translucency ⬎ 95th centile
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an active program of training and auditing of the operators was implemented, including the optimization of ultrasound machine settings to obtain satisfactory cardiac images and the use of a checklist for detailed assessment of the four-chamber and outlet views.21 The presence or absence of intracardiac echogenic foci was one of the items in the checklist. As an effect, the presence of echogenic foci was the most common reason for referral for fetal echocardiography during the study period (26% of cardiac referrals), demonstrating the high reporting rate for this finding in the population examined. The limited understanding of the mechanisms underlying increased nuchal translucency and cardiac echogenic foci makes the interpretation of the association between the two findings difficult. Although direct evidence of abnormal myocardial function has not been demonstrated in the first-trimester fetus with increased nuchal translucency, a significant proportion of fetuses with chromosomal or cardiac abnormalities exhibit absent or reversed flow in the ductus venosus during atrial contraction.26 –29 The latter is indirect evidence supporting the hypothesis of disturbed cardiac function in the etiology of increased nuchal translucency.4,30 Hence, in fetuses with congenital heart defects, thoracic tumors, and skeletal dysplasias affecting the thorax, one could postulate impaired cardiac function as the etiologic mechanism for the development of increased nuchal translucency. However, there is no satisfactory explanation for the pathogenesis of increased nuchal translucency when it occurs in fetuses subsequently shown to develop normally without a chromosomal or structural defect. In contrast to the findings with nuchal translucency, few articles have reported histologic findings in fetal hearts diagnosed with echogenic foci.31,32 These describe focal intramyocardial calcifications in the papillary muscles surrounded by fibrotic tissue. In the series by Tennstedt et al32 no myocyte necrosis, inflammatory infiltrates, or evidence of bleeding were observed to provide an explanation for the origin of the calcifications. In addition, the authors could not find any differences between fetuses with normal and abnormal karyotype. Only one article has addressed cardiac function in fetuses with echogenic foci.33 Degani and colleagues33 investigated diastolic function in 48 second-trimester fetuses with left ventricular echogenic foci by means of early ventricular or active atrial filling peak velocity ratios at Doppler fetal echocardiography. The authors showed lower ratios for the mitral as well as the tricuspid valve, suggesting that fetuses with echogenic foci may have some degree of diastolic dysfunction affecting both
902
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ventricles. However, the clinical significance of these observations remains to be determined. The finding of this study of an association between increased nuchal translucency and intracardiac echogenic foci raises the possibility that a common causal mechanism may underlie the two conditions. From animal studies, it is known that myocardial structure and function change during fetal development and that fetal myocardium is less compliant than in the adult.34 In humans, by 10 weeks’ gestation, significant changes in myocardial function have already taken place, as shown by a change from a monophasic (A wave) to a biphasic (A and E waves) Doppler pattern across the atrioventricular valves.35 Leiva et al have also shown that fetuses who showed a delay in this change during cardiac development had a worse outcome.35 It is therefore possible that if normal myocardial development and the process of myocardial maturation were delayed, persistence of a less compliant myocardium beyond 10 weeks may underlie the development of an increased nuchal translucency because of poorer cardiac diastolic function. Suboptimal cardiac function in the first trimester may lead not only to increased nuchal translucency, but also to islands of myocardial hypoxia ultimately leading to microcalcifications documented in association with echogenic foci. The effect of such an insult in the first trimester may still be detectable in the second trimester as intracardiac echogenic foci or as a disturbance of diastolic function.33 Further studies are necessary to confirm or refute this possibility. From the clinical point of view, the demonstration of an association between increased nuchal translucency measurements in the first trimester and the presence of second trimester isolated cardiac echogenic foci has relevant implications. First, if the association is confirmed, then nuchal translucency measurements and isolated echogenic foci cannot be used as independent risk factors for aneuploidy. Moreover, raised nuchal translucency values have mainly been reported to be associated with conditions implying a severe or guarded prognosis, such as chromosomal abnormalities, structural defects, or a series of genetic syndromes.36 However, previously published data suggest that a substantial proportion of fetuses with an abnormally increased nuchal translucency are born alive and have a normal postnatal development.5,37–39 This article provides a description of the association between increased nuchal translucency measurements and an apparently benign condition— cardiac echogenic foci. Delayed myocardial maturation could account for both findings. Should this prove to be correct, then a plausible explanation for the increase of nuchal translucency in normal fetuses would be available.
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14. 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;8:225–8. 15. 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. 16. Jaffe R, Cherot E, Allen T, Glantz JC. Significance of echogenic foci in the left ventricle of the fetal heart in a low-risk population. Fetal Diagn Ther 1999;14:345–7. 17. Huggon IC, Cook AC, Simpson JM, Smeeton NC, Sharland GK. Isolated echogenic foci in the fetal heart as a marker of chromosomal abnormality. Ultrasound Obstet Gynecol 2001;17:11–6. 18. 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. 19. Wax JR, Mather J, Steinfeld JD, Ingardia CJ. Fetal intracardiac echogenic foci: Current understanding and clinical significance. Obstet Gynecol Surv 2000;55:303–11. 20. Shinebourne EA, Macartney FJ, Anderson RH. Sequential chamber localization—logical approach to diagnosis in congenital heart disease. Br Heart J 1976;38:327–40. 21. Carvalho JS, Mavrides E, Shinebourne EA, Campbell S, Thilaganathan B. Improving the effectiveness of routine prenatal screening for major congenital heart defects. Heart 2002;88:387–91. 22. Royston P, Wright EM. How to construct ‘normal ranges’ for fetal variables. Ultrasound Obstet Gynecol 1998;11: 30–8. 23. Pearson EG, Hartley HO. Biometrika tables for statisticians, volume 1, 3rd ed. Cambridge, United Kingdom: Cambridge University Press, 1970. 24. Bland M. An introduction to medical statistics. Oxford, United Kingdom: Oxford University Press, 2000:240–3. 25. Bland M. An introduction to medical statistics. Oxford, United Kingdom: Oxford University Press, 2000:321–3. 26. Matias A, Gomes C, Flack N, Montenegro N, Nicolaides KH. Screening for chromosomal abnormalities at 10 –14 weeks: The role of ductus venosus blood flow. Ultrasound Obstet Gynecol 1998;12:380–4. 27. Borrell A, Antolin E, Costa D, Farre MT, Martinez JM, Fortuny A. Abnormal ductus venosus flow in trisomy 21 fetuses during early pregnancy. Am J Obstet Gynecol 1998;179:1612–7. 28. Mavrides E, Sairam S, Hollis B, Thilaganathan B. Screening for aneuploidy in the first trimester by assessment of blood flow in the ductus venosus. Br J Obstet Gynaecol 2002;109:1015–9. 29. Bilardo CM, Mu¨ller MA, Zikulnig L, Schipper M, Hecher K. Ductus venosus studies in fetuses at high risk for chromosomal or heart abnormalities: Relationship with
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36. Bilardo CM. Increased nuchal translucency and normal karyotype: Coping with uncertainty. Ultrasound Obstet Gynecol 2001;17:99–101. 37. Bilardo CM, Pajkrt E, de Graaf I, Mol BW, Bleker OP. Outcome of fetuses with enlarged nuchal translucency and normal karyotype. Ultrasound Obstet Gynecol 1998;11: 401–6. 38. Hiippala A, Eronen M, Taipale P, Salonen R, Hiilesmaa V. Fetal nuchal translucency and normal chromosomes: A long-term follow-up study. Ultrasound Obstet Gynecol 2001;18:18–22. 39. Souka AP, Krampl E, Bakalis S, Heath V, Nicolaides KH. Outcome of pregnancy in chromosomally normal fetuses with increased nuchal translucency in the first trimester. Ultrasound Obstet Gynecol 2001;18:9–17. Address reprint requests to: Julene S. Carvalho, MD, FRCPCH, Royal Brompton Hospital, Sydney Street, London SW3 6NP, United Kingdom; E-mail: j.carvalho@rbh. nthames.nhs.uk. Received August 14, 2002. Received in revised form October 4, 2002. Accepted November 7, 2002.
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