Z-score reference ranges for normal fetal heart sizes throughout pregnancy derived from fetal echocardiography Running head: Z-score reference ranges for normal fetal heart sizes Manuscript word: 3270 words of body text, 5 tables and 6 figures Xinyan Li
a,b
, MD; Qichang Zhou a,MD,PhD; Huan Huang b, MS; Xiaoxian Tian b, MS;
Qinghai Peng a,MD Department of Ultrasonography, aThe Second Xiangya Hospital, Central South University, Changsha, Hunan, P.R. China; bGuangxi Maternal and Children Health Hospital, Nanning, Guangxi, PR China. Correspondence to: Qichang Zhou MD, PhD Chairman of Ultrasonic Medicine, Professor of Internal Medicine, The Second Xiangya Hospital, Central South University 139 Renmin Road, Changsha, Hunan, China 410011, Tel:86-731-85292140, Email:[email protected].
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1002/PD.4498
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The study was supported by the State Natural Sciences Foundation of China (no. 81271593) and the Hunan Province Science & Technology program (no. 2012FJ4142, 2013SK3035). The authors have no conflicts of interest to disclose. Qichang Zhou designed the study; Xinyan Li wrote the manuscript; Xinyan Li and Huan Huang performed the measurements; Xiaoxian Tian revised part of the manuscript; and Qinghai Peng collected and analyzed the data. Bulleted statements: Assessing fetal heart size is a helpful screening method for heart disease. Nomograms of standard size hearts have been compiled by a limited number of studies and no articles regarding fetal heart size Z-scores, with the exception of two fetal heart circumference (HC) and a heart diameter (HD) studies, are available. Our results are the first to provide heart size Z-score models for the heart length (HL) and heart area (HA), rather than the HD and HC. In addition, our results are the first to suggest that HD, HL and HA may be sensitive markers to identify homozygous α-thalassemia-1 in normal fetuses.
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ABSTRACT Objective To construct Z-score reference ranges for normal fetal heart sizes throughout pregnancy. Methods This is a prospective cross-sectional investigation of 809 normal singleton fetuses from 11th week to term. Fetal transverse heart diameter (HD), heart length (HL), heart circumference (HC) and heart area (HA), were derived from two- dimensional echocardiography. The regression analyses of the mean (M) and the standard deviation (SD) for each parameter were calculated separately, using fetal somatic sizes as independent variables. A group of fetal heart diseases were assessed using these parameters. Results Strong correlations were found between fetal heart sizes and somatic sizes. Linear-cubic regression equations were each fitted to the models of the means of the heart sizes, whereas linear-quadratic equations were fitted to the models of the SDs. HD was the dependent variable that provided the highest correlation coefficient with all of the fetal sizes, followed by HL, HC and HA. All fetuses with Ebstein’s anomaly and most with homozygous α-thalassemia-1 demonstrated Z-scores reflective of increased heart sizes. Conclusion The calculation of Z-scores for heart sizes as a function of fetal somatic size is simple and may be useful for quantitative assessment of some cardiac diseases, particularly cardiomegaly caused by homozygous α-thalassemia-1.
KEYWORDS: prenatal; fetal echocardiography; Z-scores; heart size; cardiomegaly; reference ranges
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INTRODUCTION
Many structural and nonstructural heart diseases can lead to fetal cardiomegaly 1. Assessment of fetal heart size is a helpful screening method for these heart diseases. The establishment of normal cardiac size values is one of the most important prerequisites for assessing the severity of cardiomegaly in clinical practice. In the past, scholars typically assessed fetal heart size using the fetal cardiothoracic ratio (CR), an indirect marker that represents the heart-chest proportions 2, 3. However, CR has been defined and measured in a variety of manners; this variability can be confusing for the ultrasonographer and negatively influence the accuracy and reproducibility of the measurement 4. We hypothesized that measurements of fetal heart size, including the transverse heart diameter (HD), heart length (HL), heart circumference (HC) and heart area (HA), might be more direct and accurate markers for evaluation of cardiac size than conventional CR. Traditional heart size nomograms have been compiled by a limited number of studies, which typically have been based on menstrual age 5, 6. The typical issues with these traditional reference ranges and curves were described by Altman DG et al. 7. The most important concern is that the SD does not change smoothly as pregnancy proceeds, and one cannot precisely quantify the measurements using these normal values. Fetal Z-score models have been introduced by many investigators and have been used increasingly in recent years as more effective alternatives8, 9. According to these models, the Z-score is expressed as a multiple of the SD, the measurement deviates from the mean, allowing the exact quantification of the degree of cardiomegaly and a simpler comparison of the growth of cardiac sizes.
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We searched the literature and found no articles regarding fetal heart size Z-scores, except for two fetal HC studies10, 11 and one HD study12. The main objective of this prospective cross-sectional investigation was to establish a Z-score model of fetal heart size derived from two-dimensional fetal echocardiography on the basis of fetal somatic size, using the methodology introduced by Altman et al. 7 and Royston et al.8. In addition, a group of abnormal fetal hearts was tested using these reference ranges . METHODS Subjects The experimental protocol was approved by the ethics committees of the Second Xiangya Hospital and Guangxi Maternal and Children Health Hospital. This prospective cross-sectional study was conducted from September 1, 2012, to April 31, 2014, at the above-mentioned hospitals. Singleton pregnancies undergoing routine ultrasound examination from 11 to 40 weeks of gestational age were recruited. All patients signed an informed written consent form. The criteria for inclusion were as follows: (1) low risk for fetal anemia; (2) gestational age (GA) based upon regular menstruation corroborated by early ultrasonic measurement of the crown-rump length (CRL); (3) absence of fetal cardiac and extracardiac abnormalities; (4) absence of maternal diseases affecting fetal development such as diabetes mellitus and hypertension; and (5) the presence of a suitable four-chamber view. The criteria for exclusion were as follows: (1) abnormal intrauterine fetal growth; and (2) abnormal neonatal outcomes. In addition, a group of abnormal fetuses with common cardiac diseases confirmed by postmortem examination or postnatal echocardiography, or cardiomegaly caused by homozygous α-thalassemia-1 confirmed by DNA testing were
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enrolled in this study. Simple ventricular septal defects or combined congenital heart diseases or some relatively rare cases were excluded. Ultrasound equipment Two trained operators in two ultrasound units, Li Xinyan and Huang Huan, performed the necessary scans. The ultrasound systems, which were equipped with 3.5-MHz curved-array and 5.0-MHz transvaginal transducers, included a Voluson E8 (GE Healthcare, Milwaukee, WI), a Voluson 730 (GE Healthcare, Milwaukee, WI) and an Aloka 10 scanner (Aloka, Tokyo, Japan). All machines had a cine-loop that could be used to acquire the desired frozen image. Measurements All of the ultrasonographic measurements included the HD, HL, HC, HD, BPD and FL. The GA was recorded in exact weeks. The fetal heart size measurement was derived from fetal echocardiography using a standard four-chamber view during end diastole. The criteria of this view included the following: a clear display of four chambers of the heart with both atrioventricular valves closed; a complete rib length and three strong echo of the spine could be observed; and at least one pulmonary vein entering the left atrium was observed. The HD (the total transverse diameter of heart at the level of the annuli of the mitral and tricuspid valves) and the HD (from the apex to the bottom of the heart) were measured (figure 1 A). In the same image, the trackball was traced directly along the outer contour of the heart; these measurements were expressed as circumferences (HC) and areas (HA) (figure 1 B). Three separate measurements were performed in each case, and the mean value was recorded. If several measurements of a fetus were performed during a pregnancy, one measurement was randomly selected. Only one value for each fetus was used for the reference sample.
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Statistical analysis IBM SPSS package 21.0 (SPSS, Inc., Chicago, IL, USA) was used to perform the statistical analyses. First, using the HD, HL, HC and HA as the dependent variables and the GA, BPD and FL as the independent variables, the linear-cubic regression analyses of the means and SDs were performed, and the best-fitted regression equations were selected. Second, the Z-score was calculated as (observed value - fitted mean value)/fitted SD to examine the fit and adequacy of these regression models. To ascertain the normality of the Z-scores, they were plotted against the independent variables to show whether they were normally distributed. The Shapiro-Wilk W test or the Shapiro- Francia W' test were used to test for a normal distribution. If the data were not distributed normally, statistical transformation was required. Finally, we constructed the Z-score heart size models based on the fetal sizes. The statistical description of the correlation coefficients and associated P-values for the relationships of fetal heart size to fetal size were calculated. P values of < 0.05 were considered statistically significant. In addition, the mean and 5% and 95% confidence intervals of the heart size for each gestational week were calculated. Z-scores for abnormal hearts were calculated based on the constructed statistical models.
RESULTS
In total, 839 singleton pregnancies were recruited for this study. Of these cases, 20 were not included in this study due to inadequate four-chamber views. Of the excluded cases, 11 cases were between 11 and 13+6 weeks, and 9 cases were between 36 and 40 weeks. Additionally, 10 cases were excluded due to abnormal intrauterine fetal growth and abnormal neonatal outcomes. Thus, a total of 809 cases were ultimately included. Between 11-13+6
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weeks, most of the cases were scanned transabdominally, and 8 (9.8%, 8/81) cases (5 cases in week 11 and 3 cases in week 12) were scanned transvaginally. The mean age of the pregnant women was 28 (range, 18–42) years, and most of them (65.7%) were nulliparous. The gestational week at the time of measurement ranged from week 11 to week 40 (figure 2). All fetal heart and somatic size parameters increased with the duration of the pregnancy. Strong correlations were found between the fetal heart sizes and somatic sizes. The best-fitted regression equations, correlation coefficients, p and F values of the mean, and SD of the heart sizes against the fetal sizes are shown in table 1 and table 2. The linear-cubic regression equations were fitted to the models of the mean, whereas the linear-quadratic equations were fitted to the SD. The dependent variable that provided the highest correlation coefficient for the fetal size mean (0.987-0.989) was HD, followed by HL, HC and HA. The adequacy of these statistical models was tested by developing a Z-score for each variable. Because BPD was easy to obtain and permitted avoiding the use of GA if the dating criteria were not reliable, we provided the HD sample as a function of the BPD here. Figure 3 shows a scatter plot of the HD, based on BPD, with the 5th, 50th and 95th percentiles superimposed. The Z-score for the HD in terms of BPD was computed on the basis of the quadratic mean and the linear SD (see the APPENDIX). The distribution and frequency of the Z-scores suggested a Gaussian distribution (figure 4, figure 5). Finally, 78 of the 809 Z-scores were outside the limits±1.645; these number did not significantly differ from the expected 10% of the scores (P = 0.395). A normal distribution was demonstrated with the Shapiro-Wilk W test (P = 0.105). All of the regression statistical models fit the data well. To thoroughly compare our results with previous reports, we have summarized all the regression models for fetal heart
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size found in the literature in table 3. The normative heart size percentile charts for each week of gestational age are also shown in table 4. In total, 47 cases with abnormal fetal hearts (gestational age ranges from 16-28 weeks) were enrolled in this study. Table 5 presents the cardiac pathologies and the respective Z-scores for abnormal heart sizes. Among 31 cases with congenital heart diseases, all Ebstein’s anomaly cases (4 cases) exhibited a comprehensive increase in heart size Z-score, whereas all cases of hypoplastic left heart (4 cases) exhibited normal cardiac size. Only 1 abnormal Z-score was noted out of 7 atrioventricular defect cases, wherein the HD Z-score was < 2. Similarly, only 1 out of 8 cases with Tetralogy of Fallot, 1 out of 3 cases of hypoplastic right heart and 2 out of 5 cases of double outlet right ventricle exhibited Z-scores indicative of abnormal heart sizes. In contrast, the heart size Z-scores for cases of homozygous α-thalassemia-1 were increased, with Z-scores > 2 in 100% (16/16) of HD, 87.5% (14/16) of HL, 87.5% (14/16) of HC and 93.8% (15/16) of HA measurements.
DISCUSSION
Fetal congenital heart diseases, Bart's hemoglobinopathies, and non-Bart's anemia can lead to fetal cardiomegaly 13. Particularly in Southeast Asia, cardiomegaly has been shown to be one of the most common ultrasonographic features in fetuses with homozygous alpha-thalassemia-1 14. With improvements in ultrasound resolution, more accurate fetal biometric measurements are possible, even in early pregnancy. Using the Z-score increases the accuracy of echocardiographic assessments of fetal cardiomegaly. To the best of our knowledge, our results are the first to provide heart size Z-score models for HL and HA,
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rather than only for HD and HC. The Z-score of a cardiac size measurement can be calculated easily based on our statistical models (see the appendix). Previous studies have confirmed that the fetal heart could be accurately assessed during early pregnancy15, 16. Our results also demonstrated that the detection rates of suitable 4-chamber views at 11-14 weeks via a combination of transabdominal and transvaginal scans were as high as 88%. However, we were unable to address the practicality of fetal echocardiography in early pregnancy, as very few sonograms (9.8%) were performed transvaginally. Unlike traditional reference ranges for fetal parameters, the Z-scores model is derived from the basic concept that the means and SDs should change smoothly during the pregnancy and the reference percentiles should fit the data well 7,8. Royston et al. 8 stressed that fetal measurements should be based on the GA, determined as precisely as possible, in days rather than in weeks. Calculating the GA in days can minimize errors caused by recording partial weeks as full weeks, which could lead to an up to 6-day discrepancy in fetal age. Schneider et al.9 first introduced cardiac dimension Z-score models for fetal biometry instead of GA. They suggested that in cases where the GA cannot be precisely calculated, other accessible parameters such as the BPD or FL could be used to overcome the disadvantage of using the GA as the only fetal size parameter. Whereas most previous heart size studies used truncated weeks as independent variables or did not specify this variable, we constructed our statistical model on the basis of exact weeks rather than complete weeks. Moreover, we provide a relatively large sample (809 cases) of cardiac measurements over a range of GAs, from the
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11th week of pregnancy to term. Thus, we were able to monitor all of the fetuses to term and guarantee the accuracy of these predictive models. Compatible with previous studies that used various ultrasound methods 5, 6, 11, 12, our results showed that all of the cardiac size parameters increased with the GA, BPD, and FL; furthermore, strong correlations were found among the various parameters (table 1). Compared with other results, the correlation coefficients that we observed for the heart size mean were high; the highest correlation coefficient was that for HD, which was from 0.987 to 0.989. This finding might have resulted from our relatively large sample (809 cases), the use of modern ultrasound equipment and the extensive training of the two operators in our study. While most previous studies demonstrated a linear relationship with GA or BPD, our results indicated that fetal HD demonstrated a best-fitted linear-quadratic regression relationship with GA, BPD and FL. Recently, a study by Luewan S et al.12 provided quadratic equations for the mean of HD against GA and BPD, head circumferences and Z-scores. In another preliminary study of embryonic HD17, a best-fitted cubic regression equation was produced. However, it should be mentioned that method of HD measurement is used differently. Some authors 5,7,15,17 measured HD at the level of the AV valve plane, similar to this study, whereas other authors 12 have measured below the valve orifices, as this is where the authors noted the greatest dimension. This difference will result in some discrepancies among studies. As shown in table 3, the fetal HC is the best-studied cardiac size parameter in the literature. Lee et al. 10 and Traisrisilp et al. 11 also performed further regression analysis of the SD of the HC, which is essential to the construction of z-score statistical models. Previous results have consistently developed linear growth curves for the fetal HC; however, in our study, as well
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as in the study by Traisrisilp et al.11 (which was derived from a cardio–spatiotemporal image correlation), the best-fit model against the fetal sizes was not entirely linear. Our fetal HC Z-score models were adequately fitted to the raw data as well, with a higher coefficient relationship than in previous reports. Regarding the fetal HA, all of the previous authors agreed that this parameter increases linearly with the GA and BPD. Nevertheless, in our study, cubic regression equations, rather than a linear equation, best fit the raw data in terms of fetal somatic sizes. The discrepancies between our results and the other studies may have occurred because we used slightly different methods and included subjects from a different national population; additionally, the present study had a relatively larger sample size and included fetuses with a higher GA. No concrete information regarding the fetal HL has been available until now. We compared our values with other studies of cardiac size from the 11th to the 15th week of gestation, where many results are available and comparable. The mean value of HD that we predicted was somewhat lower than that of Gembruch et al,5 higher than that of Bronshtein et al. 6 and similar to that of Smrcek et al 15. The mean HC that we predicted at weeks 11-15 was slightly higher than in previous studies. Regarding HA, our results were a bit higher in the 11th week and lower in the 15th week than those reported by other studies. Variations in nationality and ultrasound technique may have contributed to this difference, as some authors did not specifically perform their measurements during end diastole. We only used a small sample size of fetal hearts with confirmed abnormalities to assess the heart size Z-score reference ranges. We excluded hearts with simple ventricular septal defects and combined congenital heart diseases because the former may
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have a normal heart size, whereas the latter may have a complex impact on these parameters. With the exception of 4 cases of Ebstein’s anomaly that exhibited a comprehensive increase in heart size Z-scores, we observed that the heart size of most common congenital heart diseases were normal, whereas increased heart size, in particular HD and HA, were always noted in cases of homozygous α-thalassemia-1. These findings suggested that the heart size Z-score might not be a useful tool for the diagnosis of most congenital heart diseases, such as atrioventricular defects, Tetralogy of Fallot, hypoplastic left/right heart and double outlet right ventricle. However, heart size Z-scores may serve as new sensitive markers to identify homozygous α-thalassemia-1. In fact, in a recent report, the fetal HC has been used as a predictor of homozygous α-thalassemia-1 at midpregnancy, with a sensitivity and specificity of 86.4% and 78.1%, respectively20. One limitation of this study was that the inter- and intra-observer variability of the two operators’ measurements was not assessed, although both observers were well trained. Another limitation involved the fact that most newborns have not undergone detailed echocardiography. However, considering the accuracy of fetal echocardiography, this fact is unlikely to significantly alter the ultimate statistical models. In summary, the fetal heart sizes were strongly associated with the fetal somatic size. The calculation of Z-scores for heart sizes is simple, accurate and potentially very useful in clinical applications. Deviations from these normative values may raise the suspicion of some types of fetal cardiac diseases, in particular cardiomegaly secondary to homozygous α-thalassemia-1. However, the effectiveness of these parameters must be further investigated.
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Acknowledgments
We thank everyone in the ultrasound departments in the Second Xiangya Hospital and the Guangxi Maternal and Children Health Hospital for their support. All of the authors report no conflicts of interest. This study was supported by the State Natural Sciences Foundation of China (no. 81271593) and the Hunan Province Science & Technology program (no. 2012FJ4142, 2013SK3035). Appendix An example of the heart size Z-score calculation BPD = 35 mm HD =15.8 mm From Table 1, the fitted mean value of HD =1.152 + 0.2644 * 35+ 0.00168 * 35 * 35 = 12.5 mm From Table 2, the fitted SD = -0.130 + 0.0298 * 35 = 0.91 mm z = (observed value - fitted mean value)/fitted SD = (15.8−12.5)/0.91= 3.6 The HD Z-score was +3.6 SD above the fitted mean value for BPD; therefore, the fetus was considered to have cardiomegaly. Because both parents are α-thalassemia-1 carriers, we predicted that the fetus might have homozygous-α-thalassemia-1; subsequent amniocentesis and DNA testing confirmed this finding.
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REFERENCES
1 Chaoui R, Bollmann R, Göldner B, et al. Fetal cardiomegaly: echocardiographic findings and outcome in 19 cases. Fetal Diagn Ther 1994; 9(2):92-104. 2 Paladini D, Chita S, Allan LD. Prenatal measurement of the cardiothoracic ratio in evaluation of heart disease. Arch Dis Child 1990; 65:20–23. 3 Leung KY, Liao C, Li QM, et al. A new strategy for prenatal diagnosis of homozygous alpha(0)-thalassemia. Ultrasound Obstet Gynecol 2006; 28: 173-7. 4 Awadh AM, Prefumo F, Bland JM, et al. Assessment of the intraobserver variability in the measurement of fetal cardiothoracic ratio using ellipse and diameter methods. Ultrasound Obstet Gynecol 2006 Jul;28(1):53-6. 5 Gembruch U, Shi C, Smrcek JM. Biometry of the fetal heart between 10 and 17 weeks of gestation. Fetal Diagn Ther 2000; 15(1):20-31. 6 Bronshtein M, Siegler E, Eshcoli Z, et al. Transvaginal ultrasound measurements of the fetal heart at 11 to 17 weeks of gestation. Am J Perinatol 1992; 9:38–42. 7 Altman DG, Chitty LS. Charts of fetal size. 1. Methodology.Br J Obstet Gynaecol. 1994; 101(1):29-34. 8 Royston P, Wright EM. How to construct “normal ranges” for fetal variables. Ultrasound Obstet Gynecol 1998; 11:30–38. 9 Schneider C, McCrindle BW, Carvalho JS, et al. Development of z-scores for fetal cardiac dimensions from echocardiography. Ultrasound Obstet Gynecol 2005; 26: 599–605. 10 Lee W, Riggs T, Amula V, et al. Fetal echocardiography: z-score reference ranges for a large patient population. Ultrasound Obstet Gynecol 2010; 35:28–34.
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11 Traisrisilp K, Tongprasert F, Srisupundit K, et al. Reference Ranges for the Fetal Cardiac Circumference Derived by Cardio–Spatiotemporal Image Correlation From 14 to 40 Weeks’ Gestation. J Ultrasound Med 2011; 30:1191–1196. 12 Luewan S, Yanase Y, Tongprasert F, Srisupundit K, Tongsong T. Fetal cardiac dimensions at 14-40 weeks' gestation obtained using cardio-STIC-M. Ultrasound Obstet Gynecol. 2011 ;37(4):416-22. 13 Wuttikonsammakit P, Uerpairojkit B, Tanawattanacharoen S.Causes and consequences of 93 fetuses with cardiomegaly in a tertiary center in Thailand. Arch Gynecol Obstet. 2011; 283(4):701-6. doi: 10.1007/s00404-010-1426-0. Epub 2010 Mar 19. 14 Tongsong T, Wanapirak C, Srisomboon J, et al. Antenatal sonographic features of 100 alpha-thalassemia hydrops fetalis fetuses. Clin Ultrasound 1996; 24(2):73-7. 15 Smrcek JM, Berg C, Geipel A, et al. Early fetal echocardiography: heart biometry and visualization of cardiac structures between 10 and 15 weeks' gestation. J Ultrasound Med. 2006 Feb;25(2):173-82; quiz 183-5. 16 McAuliffe FM, Trines J, Nield LE, et al. Early fetal echocardiography--a reliable prenatal diagnosis tool. Am J Obstet Gynecol. 2005 Sep;193(3 Pt 2):1253-9. 17 Hata T, Senoh D, Hata K, et al. Intrauterine sonographic assessments of embryonic heart diameter. Hum Reprod. 1997 Oct;12(10):2286-91. 18 Guariglia L, Rosati P, Bartolozzi F. Cardiac circumference measurement: possible screening tool in early pregnancy for anomalous cardiac development. Fetal Diagn Ther. 2006;21(1):134-9.
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19 JORDAAN, HAROLD V. F. MD, PhD. Cardiac size during prenatal development. Obstetrics Gynecology. 1987; 69(6):854-8. 20 Siwawong W, Tongprasert F, Srisupundit K, Luewan S, Tongsong T. Fetal cardiac circumference derived by spatiotemporal image correlation as a predictor of fetal hemoglobin Bart disease at midpregnancy. J Ultrasound Med. 2013;32(8):1483-8.
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Figure 1 A standard four-chamber view during end diastole at 21 gestational weeks. Panel A shows the measurements of HD and HL, and Panel B shows the measurements of HC and HA.
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Figure 2 Numbers of cases in each gestational week.
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Figure 3 A scatter plot of the HD, based on BPD, with the 5th, 50th and 95th percentiles superimposed.
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Figure 4 A scatter plot of the Z-score plotted against the BPD, with tramlines at 1.96, 0, and -1.96.
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Figure 5 The frequency of the Z-score with an approximately normal distribution.
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Table 1. Regression analysis of fetal heart sizes based on GA, BPD and FL.
Fetal heart
Regression equation
parameters
R
P
F test
value
GA, wks HD, mm
Y=-8.336+1.269GA
0.988
a,b
, MD; Qichang Zhou a,MD,PhD; Huan Huang b, MS; Xiaoxian Tian b, MS;
Qinghai Peng a,MD Department of Ultrasonography, aThe Second Xiangya Hospital, Central South University, Changsha, Hunan, P.R. China; bGuangxi Maternal and Children Health Hospital, Nanning, Guangxi, PR China. Correspondence to: Qichang Zhou MD, PhD Chairman of Ultrasonic Medicine, Professor of Internal Medicine, The Second Xiangya Hospital, Central South University 139 Renmin Road, Changsha, Hunan, China 410011, Tel:86-731-85292140, Email:[email protected].
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1002/PD.4498
This article is protected by copyright. All rights reserved.
The study was supported by the State Natural Sciences Foundation of China (no. 81271593) and the Hunan Province Science & Technology program (no. 2012FJ4142, 2013SK3035). The authors have no conflicts of interest to disclose. Qichang Zhou designed the study; Xinyan Li wrote the manuscript; Xinyan Li and Huan Huang performed the measurements; Xiaoxian Tian revised part of the manuscript; and Qinghai Peng collected and analyzed the data. Bulleted statements: Assessing fetal heart size is a helpful screening method for heart disease. Nomograms of standard size hearts have been compiled by a limited number of studies and no articles regarding fetal heart size Z-scores, with the exception of two fetal heart circumference (HC) and a heart diameter (HD) studies, are available. Our results are the first to provide heart size Z-score models for the heart length (HL) and heart area (HA), rather than the HD and HC. In addition, our results are the first to suggest that HD, HL and HA may be sensitive markers to identify homozygous α-thalassemia-1 in normal fetuses.
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ABSTRACT Objective To construct Z-score reference ranges for normal fetal heart sizes throughout pregnancy. Methods This is a prospective cross-sectional investigation of 809 normal singleton fetuses from 11th week to term. Fetal transverse heart diameter (HD), heart length (HL), heart circumference (HC) and heart area (HA), were derived from two- dimensional echocardiography. The regression analyses of the mean (M) and the standard deviation (SD) for each parameter were calculated separately, using fetal somatic sizes as independent variables. A group of fetal heart diseases were assessed using these parameters. Results Strong correlations were found between fetal heart sizes and somatic sizes. Linear-cubic regression equations were each fitted to the models of the means of the heart sizes, whereas linear-quadratic equations were fitted to the models of the SDs. HD was the dependent variable that provided the highest correlation coefficient with all of the fetal sizes, followed by HL, HC and HA. All fetuses with Ebstein’s anomaly and most with homozygous α-thalassemia-1 demonstrated Z-scores reflective of increased heart sizes. Conclusion The calculation of Z-scores for heart sizes as a function of fetal somatic size is simple and may be useful for quantitative assessment of some cardiac diseases, particularly cardiomegaly caused by homozygous α-thalassemia-1.
KEYWORDS: prenatal; fetal echocardiography; Z-scores; heart size; cardiomegaly; reference ranges
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INTRODUCTION
Many structural and nonstructural heart diseases can lead to fetal cardiomegaly 1. Assessment of fetal heart size is a helpful screening method for these heart diseases. The establishment of normal cardiac size values is one of the most important prerequisites for assessing the severity of cardiomegaly in clinical practice. In the past, scholars typically assessed fetal heart size using the fetal cardiothoracic ratio (CR), an indirect marker that represents the heart-chest proportions 2, 3. However, CR has been defined and measured in a variety of manners; this variability can be confusing for the ultrasonographer and negatively influence the accuracy and reproducibility of the measurement 4. We hypothesized that measurements of fetal heart size, including the transverse heart diameter (HD), heart length (HL), heart circumference (HC) and heart area (HA), might be more direct and accurate markers for evaluation of cardiac size than conventional CR. Traditional heart size nomograms have been compiled by a limited number of studies, which typically have been based on menstrual age 5, 6. The typical issues with these traditional reference ranges and curves were described by Altman DG et al. 7. The most important concern is that the SD does not change smoothly as pregnancy proceeds, and one cannot precisely quantify the measurements using these normal values. Fetal Z-score models have been introduced by many investigators and have been used increasingly in recent years as more effective alternatives8, 9. According to these models, the Z-score is expressed as a multiple of the SD, the measurement deviates from the mean, allowing the exact quantification of the degree of cardiomegaly and a simpler comparison of the growth of cardiac sizes.
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We searched the literature and found no articles regarding fetal heart size Z-scores, except for two fetal HC studies10, 11 and one HD study12. The main objective of this prospective cross-sectional investigation was to establish a Z-score model of fetal heart size derived from two-dimensional fetal echocardiography on the basis of fetal somatic size, using the methodology introduced by Altman et al. 7 and Royston et al.8. In addition, a group of abnormal fetal hearts was tested using these reference ranges . METHODS Subjects The experimental protocol was approved by the ethics committees of the Second Xiangya Hospital and Guangxi Maternal and Children Health Hospital. This prospective cross-sectional study was conducted from September 1, 2012, to April 31, 2014, at the above-mentioned hospitals. Singleton pregnancies undergoing routine ultrasound examination from 11 to 40 weeks of gestational age were recruited. All patients signed an informed written consent form. The criteria for inclusion were as follows: (1) low risk for fetal anemia; (2) gestational age (GA) based upon regular menstruation corroborated by early ultrasonic measurement of the crown-rump length (CRL); (3) absence of fetal cardiac and extracardiac abnormalities; (4) absence of maternal diseases affecting fetal development such as diabetes mellitus and hypertension; and (5) the presence of a suitable four-chamber view. The criteria for exclusion were as follows: (1) abnormal intrauterine fetal growth; and (2) abnormal neonatal outcomes. In addition, a group of abnormal fetuses with common cardiac diseases confirmed by postmortem examination or postnatal echocardiography, or cardiomegaly caused by homozygous α-thalassemia-1 confirmed by DNA testing were
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enrolled in this study. Simple ventricular septal defects or combined congenital heart diseases or some relatively rare cases were excluded. Ultrasound equipment Two trained operators in two ultrasound units, Li Xinyan and Huang Huan, performed the necessary scans. The ultrasound systems, which were equipped with 3.5-MHz curved-array and 5.0-MHz transvaginal transducers, included a Voluson E8 (GE Healthcare, Milwaukee, WI), a Voluson 730 (GE Healthcare, Milwaukee, WI) and an Aloka 10 scanner (Aloka, Tokyo, Japan). All machines had a cine-loop that could be used to acquire the desired frozen image. Measurements All of the ultrasonographic measurements included the HD, HL, HC, HD, BPD and FL. The GA was recorded in exact weeks. The fetal heart size measurement was derived from fetal echocardiography using a standard four-chamber view during end diastole. The criteria of this view included the following: a clear display of four chambers of the heart with both atrioventricular valves closed; a complete rib length and three strong echo of the spine could be observed; and at least one pulmonary vein entering the left atrium was observed. The HD (the total transverse diameter of heart at the level of the annuli of the mitral and tricuspid valves) and the HD (from the apex to the bottom of the heart) were measured (figure 1 A). In the same image, the trackball was traced directly along the outer contour of the heart; these measurements were expressed as circumferences (HC) and areas (HA) (figure 1 B). Three separate measurements were performed in each case, and the mean value was recorded. If several measurements of a fetus were performed during a pregnancy, one measurement was randomly selected. Only one value for each fetus was used for the reference sample.
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Statistical analysis IBM SPSS package 21.0 (SPSS, Inc., Chicago, IL, USA) was used to perform the statistical analyses. First, using the HD, HL, HC and HA as the dependent variables and the GA, BPD and FL as the independent variables, the linear-cubic regression analyses of the means and SDs were performed, and the best-fitted regression equations were selected. Second, the Z-score was calculated as (observed value - fitted mean value)/fitted SD to examine the fit and adequacy of these regression models. To ascertain the normality of the Z-scores, they were plotted against the independent variables to show whether they were normally distributed. The Shapiro-Wilk W test or the Shapiro- Francia W' test were used to test for a normal distribution. If the data were not distributed normally, statistical transformation was required. Finally, we constructed the Z-score heart size models based on the fetal sizes. The statistical description of the correlation coefficients and associated P-values for the relationships of fetal heart size to fetal size were calculated. P values of < 0.05 were considered statistically significant. In addition, the mean and 5% and 95% confidence intervals of the heart size for each gestational week were calculated. Z-scores for abnormal hearts were calculated based on the constructed statistical models.
RESULTS
In total, 839 singleton pregnancies were recruited for this study. Of these cases, 20 were not included in this study due to inadequate four-chamber views. Of the excluded cases, 11 cases were between 11 and 13+6 weeks, and 9 cases were between 36 and 40 weeks. Additionally, 10 cases were excluded due to abnormal intrauterine fetal growth and abnormal neonatal outcomes. Thus, a total of 809 cases were ultimately included. Between 11-13+6
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weeks, most of the cases were scanned transabdominally, and 8 (9.8%, 8/81) cases (5 cases in week 11 and 3 cases in week 12) were scanned transvaginally. The mean age of the pregnant women was 28 (range, 18–42) years, and most of them (65.7%) were nulliparous. The gestational week at the time of measurement ranged from week 11 to week 40 (figure 2). All fetal heart and somatic size parameters increased with the duration of the pregnancy. Strong correlations were found between the fetal heart sizes and somatic sizes. The best-fitted regression equations, correlation coefficients, p and F values of the mean, and SD of the heart sizes against the fetal sizes are shown in table 1 and table 2. The linear-cubic regression equations were fitted to the models of the mean, whereas the linear-quadratic equations were fitted to the SD. The dependent variable that provided the highest correlation coefficient for the fetal size mean (0.987-0.989) was HD, followed by HL, HC and HA. The adequacy of these statistical models was tested by developing a Z-score for each variable. Because BPD was easy to obtain and permitted avoiding the use of GA if the dating criteria were not reliable, we provided the HD sample as a function of the BPD here. Figure 3 shows a scatter plot of the HD, based on BPD, with the 5th, 50th and 95th percentiles superimposed. The Z-score for the HD in terms of BPD was computed on the basis of the quadratic mean and the linear SD (see the APPENDIX). The distribution and frequency of the Z-scores suggested a Gaussian distribution (figure 4, figure 5). Finally, 78 of the 809 Z-scores were outside the limits±1.645; these number did not significantly differ from the expected 10% of the scores (P = 0.395). A normal distribution was demonstrated with the Shapiro-Wilk W test (P = 0.105). All of the regression statistical models fit the data well. To thoroughly compare our results with previous reports, we have summarized all the regression models for fetal heart
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size found in the literature in table 3. The normative heart size percentile charts for each week of gestational age are also shown in table 4. In total, 47 cases with abnormal fetal hearts (gestational age ranges from 16-28 weeks) were enrolled in this study. Table 5 presents the cardiac pathologies and the respective Z-scores for abnormal heart sizes. Among 31 cases with congenital heart diseases, all Ebstein’s anomaly cases (4 cases) exhibited a comprehensive increase in heart size Z-score, whereas all cases of hypoplastic left heart (4 cases) exhibited normal cardiac size. Only 1 abnormal Z-score was noted out of 7 atrioventricular defect cases, wherein the HD Z-score was < 2. Similarly, only 1 out of 8 cases with Tetralogy of Fallot, 1 out of 3 cases of hypoplastic right heart and 2 out of 5 cases of double outlet right ventricle exhibited Z-scores indicative of abnormal heart sizes. In contrast, the heart size Z-scores for cases of homozygous α-thalassemia-1 were increased, with Z-scores > 2 in 100% (16/16) of HD, 87.5% (14/16) of HL, 87.5% (14/16) of HC and 93.8% (15/16) of HA measurements.
DISCUSSION
Fetal congenital heart diseases, Bart's hemoglobinopathies, and non-Bart's anemia can lead to fetal cardiomegaly 13. Particularly in Southeast Asia, cardiomegaly has been shown to be one of the most common ultrasonographic features in fetuses with homozygous alpha-thalassemia-1 14. With improvements in ultrasound resolution, more accurate fetal biometric measurements are possible, even in early pregnancy. Using the Z-score increases the accuracy of echocardiographic assessments of fetal cardiomegaly. To the best of our knowledge, our results are the first to provide heart size Z-score models for HL and HA,
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rather than only for HD and HC. The Z-score of a cardiac size measurement can be calculated easily based on our statistical models (see the appendix). Previous studies have confirmed that the fetal heart could be accurately assessed during early pregnancy15, 16. Our results also demonstrated that the detection rates of suitable 4-chamber views at 11-14 weeks via a combination of transabdominal and transvaginal scans were as high as 88%. However, we were unable to address the practicality of fetal echocardiography in early pregnancy, as very few sonograms (9.8%) were performed transvaginally. Unlike traditional reference ranges for fetal parameters, the Z-scores model is derived from the basic concept that the means and SDs should change smoothly during the pregnancy and the reference percentiles should fit the data well 7,8. Royston et al. 8 stressed that fetal measurements should be based on the GA, determined as precisely as possible, in days rather than in weeks. Calculating the GA in days can minimize errors caused by recording partial weeks as full weeks, which could lead to an up to 6-day discrepancy in fetal age. Schneider et al.9 first introduced cardiac dimension Z-score models for fetal biometry instead of GA. They suggested that in cases where the GA cannot be precisely calculated, other accessible parameters such as the BPD or FL could be used to overcome the disadvantage of using the GA as the only fetal size parameter. Whereas most previous heart size studies used truncated weeks as independent variables or did not specify this variable, we constructed our statistical model on the basis of exact weeks rather than complete weeks. Moreover, we provide a relatively large sample (809 cases) of cardiac measurements over a range of GAs, from the
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11th week of pregnancy to term. Thus, we were able to monitor all of the fetuses to term and guarantee the accuracy of these predictive models. Compatible with previous studies that used various ultrasound methods 5, 6, 11, 12, our results showed that all of the cardiac size parameters increased with the GA, BPD, and FL; furthermore, strong correlations were found among the various parameters (table 1). Compared with other results, the correlation coefficients that we observed for the heart size mean were high; the highest correlation coefficient was that for HD, which was from 0.987 to 0.989. This finding might have resulted from our relatively large sample (809 cases), the use of modern ultrasound equipment and the extensive training of the two operators in our study. While most previous studies demonstrated a linear relationship with GA or BPD, our results indicated that fetal HD demonstrated a best-fitted linear-quadratic regression relationship with GA, BPD and FL. Recently, a study by Luewan S et al.12 provided quadratic equations for the mean of HD against GA and BPD, head circumferences and Z-scores. In another preliminary study of embryonic HD17, a best-fitted cubic regression equation was produced. However, it should be mentioned that method of HD measurement is used differently. Some authors 5,7,15,17 measured HD at the level of the AV valve plane, similar to this study, whereas other authors 12 have measured below the valve orifices, as this is where the authors noted the greatest dimension. This difference will result in some discrepancies among studies. As shown in table 3, the fetal HC is the best-studied cardiac size parameter in the literature. Lee et al. 10 and Traisrisilp et al. 11 also performed further regression analysis of the SD of the HC, which is essential to the construction of z-score statistical models. Previous results have consistently developed linear growth curves for the fetal HC; however, in our study, as well
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as in the study by Traisrisilp et al.11 (which was derived from a cardio–spatiotemporal image correlation), the best-fit model against the fetal sizes was not entirely linear. Our fetal HC Z-score models were adequately fitted to the raw data as well, with a higher coefficient relationship than in previous reports. Regarding the fetal HA, all of the previous authors agreed that this parameter increases linearly with the GA and BPD. Nevertheless, in our study, cubic regression equations, rather than a linear equation, best fit the raw data in terms of fetal somatic sizes. The discrepancies between our results and the other studies may have occurred because we used slightly different methods and included subjects from a different national population; additionally, the present study had a relatively larger sample size and included fetuses with a higher GA. No concrete information regarding the fetal HL has been available until now. We compared our values with other studies of cardiac size from the 11th to the 15th week of gestation, where many results are available and comparable. The mean value of HD that we predicted was somewhat lower than that of Gembruch et al,5 higher than that of Bronshtein et al. 6 and similar to that of Smrcek et al 15. The mean HC that we predicted at weeks 11-15 was slightly higher than in previous studies. Regarding HA, our results were a bit higher in the 11th week and lower in the 15th week than those reported by other studies. Variations in nationality and ultrasound technique may have contributed to this difference, as some authors did not specifically perform their measurements during end diastole. We only used a small sample size of fetal hearts with confirmed abnormalities to assess the heart size Z-score reference ranges. We excluded hearts with simple ventricular septal defects and combined congenital heart diseases because the former may
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have a normal heart size, whereas the latter may have a complex impact on these parameters. With the exception of 4 cases of Ebstein’s anomaly that exhibited a comprehensive increase in heart size Z-scores, we observed that the heart size of most common congenital heart diseases were normal, whereas increased heart size, in particular HD and HA, were always noted in cases of homozygous α-thalassemia-1. These findings suggested that the heart size Z-score might not be a useful tool for the diagnosis of most congenital heart diseases, such as atrioventricular defects, Tetralogy of Fallot, hypoplastic left/right heart and double outlet right ventricle. However, heart size Z-scores may serve as new sensitive markers to identify homozygous α-thalassemia-1. In fact, in a recent report, the fetal HC has been used as a predictor of homozygous α-thalassemia-1 at midpregnancy, with a sensitivity and specificity of 86.4% and 78.1%, respectively20. One limitation of this study was that the inter- and intra-observer variability of the two operators’ measurements was not assessed, although both observers were well trained. Another limitation involved the fact that most newborns have not undergone detailed echocardiography. However, considering the accuracy of fetal echocardiography, this fact is unlikely to significantly alter the ultimate statistical models. In summary, the fetal heart sizes were strongly associated with the fetal somatic size. The calculation of Z-scores for heart sizes is simple, accurate and potentially very useful in clinical applications. Deviations from these normative values may raise the suspicion of some types of fetal cardiac diseases, in particular cardiomegaly secondary to homozygous α-thalassemia-1. However, the effectiveness of these parameters must be further investigated.
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Acknowledgments
We thank everyone in the ultrasound departments in the Second Xiangya Hospital and the Guangxi Maternal and Children Health Hospital for their support. All of the authors report no conflicts of interest. This study was supported by the State Natural Sciences Foundation of China (no. 81271593) and the Hunan Province Science & Technology program (no. 2012FJ4142, 2013SK3035). Appendix An example of the heart size Z-score calculation BPD = 35 mm HD =15.8 mm From Table 1, the fitted mean value of HD =1.152 + 0.2644 * 35+ 0.00168 * 35 * 35 = 12.5 mm From Table 2, the fitted SD = -0.130 + 0.0298 * 35 = 0.91 mm z = (observed value - fitted mean value)/fitted SD = (15.8−12.5)/0.91= 3.6 The HD Z-score was +3.6 SD above the fitted mean value for BPD; therefore, the fetus was considered to have cardiomegaly. Because both parents are α-thalassemia-1 carriers, we predicted that the fetus might have homozygous-α-thalassemia-1; subsequent amniocentesis and DNA testing confirmed this finding.
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REFERENCES
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Figure 1 A standard four-chamber view during end diastole at 21 gestational weeks. Panel A shows the measurements of HD and HL, and Panel B shows the measurements of HC and HA.
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Figure 2 Numbers of cases in each gestational week.
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Figure 3 A scatter plot of the HD, based on BPD, with the 5th, 50th and 95th percentiles superimposed.
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Figure 4 A scatter plot of the Z-score plotted against the BPD, with tramlines at 1.96, 0, and -1.96.
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Figure 5 The frequency of the Z-score with an approximately normal distribution.
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Table 1. Regression analysis of fetal heart sizes based on GA, BPD and FL.
Fetal heart
Regression equation
parameters
R
P
F test
value
GA, wks HD, mm
Y=-8.336+1.269GA
0.988
