Reference Ranges for the Fetal Cardiac Circumference Derived by Cardio Spatiotemporal Image Correlation From 14 to 40 Weeks Gestation

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1 ORIGINAL RESEARCH Reference Ranges for the Fetal Cardiac Circumference Derived by Cardio Spatiotemporal Image Correlation From 14 to 40 Weeks Gestation Kuntharee Traisrisilp, MD, Fuanglada Tongprasert, MD, Kasemsri Srisupundit, MD, Suchaya Luewan, MD, Theera Tongsong, MD Objectives The purpose of this study was to construct reference ranges for the fetal cardiac circumference derived from volume data sets obtained by cardio spatiotemporal image correlation. Methods A prospective descriptive study was conducted on normal singleton pregnancies with certain dates from 14 to 40 weeks gestation. All underwent cardio spatiotemporal image correlation to acquire volume data sets for subsequent analysis. Cardiac circumferences were measured offline in a multiplanar view with 4-dimensional imaging software. The reference ranges were constructed against gestational weeks and the biparietal diameter as independent variables, using regression models for both the mean and SD. Results A total of 678 satisfactory volumes were analyzed. Normal reference ranges for predicting means and SDs of the fetal cardiac circumference were established based on best-fitted equations. The mean cardiac circumference (millimeters) was modeled as a function of gestational age (weeks) and biparietal diameter (centimeters) as follows: cardiac circumference = gestational age gestational age 2 (SD = gestational age) and biparietal diameter (SD = biparietal diameter). Equations for z score calculation were also provided, and percentile charts for predicting the cardiac circumference at various points of gestational age and biparietal diameter were constructed. Conclusions Normal reference ranges and z scores for the fetal cardiac circumference have been provided. These normative data may be useful tools for assessment of fetal cardiac size, especially in cardiomegaly due to fetal anemia. Key Words fetal cardiac circumference; 4-dimensional sonography; prenatal; reference range; spatiotemporal image correlation; z scores Received February 10, 2011, from the Department of Obstetrics and Gynecology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand. Revision requested March 2, Revised manuscript accepted for publication April 6, This work was supported by the Thai Research Fund and the National Research University Project under Thailand s Office of the Higher Education Commission. Address correspondence to Theera Tongsong, MD, Department of Obstetrics and Gynecology, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand. ttongson@mail.med.cmu.ac.th A ssessment of fetal cardiac size is essential in prenatal diagnosis of various cardiac anomalies, especially cardiomegaly secondary to fetal anemia of various causes. For example, our experience shows that the cardiac diameter for cardiac size assessment is very helpful in early diagnosis of cardiomegaly due to hemoglobin Bart disease. 1 Theoretically, measurement of the cardiac circumference is certainly more accurate than the cardiac diameter because it better represents the cardiac size in all dimensions. In the past, we rarely measured the cardiac circumference because it is more time-consuming and subject to measurement error because of a poor border outline, especially in early gestation. Therefore, a only few studies on cardiac circumference have been 2011 by the American Institute of Ultrasound in Medicine J Ultrasound Med 2011; 30:

2 published. 2 6 Additionally, most included only short gestational periods or small sample sizes. Moreover, only a study reported by Lee et al 5 provided z scores as a quantitative assessment for clinical purposes. Importantly, z scores allow the examiner to quantify the cardiac size without the limitations of traditional confidence intervals. However, the study by Lee et al 5 was based on a retrospective database assessment, and their z score reference ranges were derived from 2-dimensional fetal echocardiography, with which it is relatively difficult to get a precise plane for a cardiac study compared to 4-dimensional sonography with spatiotemporal image correlation (cardio spatiotemporal image correlation). With cardio spatiotemporal image correlation, the focused structures can be shown in all dimensions, leading to more precise measurement. 7 Therefore, we conducted this prospective study to develop z scores and percentile reference ranges for the fetal cardiac circumference derived from cardio spatiotemporal image correlation. To our best knowledge, reference ranges for the cardiac circumference derived from cardio spatiotemporal image correlation have not been reported previously. Materials and Methods This prospective descriptive study was conducted between September 1, 2007, and October 31, 2010, at Maharaj Nakorn Chiang Mai Hospital, Chiang Mai University, with approval from the institute s Ethics Committee. Normal singleton pregnancies were recruited from the antenatal care unit, and written informed consent was obtained. The inclusion criteria were as follows: (1) gestational age between 14 and 40 weeks, (2) accurate gestational age based on sonographic fetal biometric measurements in the first half of pregnancy and consistent with a reliable menstrual period, and (3) low-risk pregnancies without known medical or obstetric complications. The exclusion criteria were as follows: (1) multifetal pregnancies, (2) fetal anomalies, (3) abnormal fetal growth (fetal growth restriction [<10th percentile] or macrosomia [>90th percentile]), and (4) inability to obtain satisfactory cardio spatiotemporal image correlation volume data sets. All patients underwent standard sonographic examinations, including fetal biometric measurements with an anatomic survey, and cardio spatiotemporal image correlation volumes were acquired using a real-time machine with 2- to 5-MHz curvilinear transabdominal transducers (Voluson E8; GE Healthcare, Milwaukee, WI). The volume data sets were acquired with transverse sweeps through the fetal chest, which included the proper apical and transverse 4-chamber views. Acquisition times ranged from 7.5 to 15 seconds, and acquisition angles ranged from 20 to 40 depending on the gestational age and cardiac size. All of the cardio spatiotemporal image correlation volumes were stored in the ultrasound machine s hard drive for subsequent offline analysis. The volume data set analysis was systematically performed to identify the exact 4-chamber view, according to instructions described elsewhere, 8,9 using 4D View version 9.0 software (GE Healthcare, Zipf, Austria), as shown in Figure 1. The analysis is summarized as follows: Dynamic images of the fetal heart were simultaneously visualized in the 3 orthogonal planes on panels A, B, and C of the multiplanar views. Images of the 4-chamber view were minutely maneuvered by moving the reference dot and rotating the fetal heart around the 3 orthogonal axes (x, y, and z) to get the interventricular septum in the exact horizontal plane in all 3 panels. The proper image could be checked by showing that the interventricular septum in panel A was on the same line as in panel B, and a total en face view of the interventricular septum was visualized in panel C (Figure 1). The typical 4-chamber view in panel A was frozen at end-diastole and then was displayed and magnified as a single image on the screen. The cardiac circumference was measured at end-diastole using the area point or area trace function in 4D View. Regression analysis of the fetal cardiac circumference was performed to identify the best-fitted equation using SPSS version 17.0 software (SPSS Inc, Chicago, IL). The procedure followed instructions published by Royston and Wright. 10 Briefly, regression models were fitted separately to the mean and SD of the cardiac circumference (depen- Figure 1. Fetal cardiac circumference displayed in multiplanar views of a cardio spatiotemporal image correlation volume in the 4-chamber view. Note that the interventricular septum in panel A is set to be on the same line in panel B to get the exact 4-chamber view in panel A J Ultrasound Med 2011; 30:

3 dent variables) to generate the best-fitted regression equations. The best-fitted models for the SD were derived from regression of scaled absolute residuals which were obtained as: scaled absolute residual = 1.25 absolute (measured value predicted value). Normality and goodness-of-fit regression models were assessed by examination of the scatter patterns of points relative to fitted means and SDs, expressed as z scores (measured value estimated mean/estimated SD). The z scores were tested for normality using the Sharpiro-Wilk W test and Q-Q plots. Percentile curves and tables of reference ranges were constructed by the formula percentile = mean + K SD, where K was the corresponding percentile of the standard Gaussian distribution. Results A total of 710 cardio spatiotemporal image correlation volumes were successfully acquired and available for offline analysis; however, only 678 volume data sets from 678 fetuses had satisfactory cardiac circumference measurements. The mean maternal age ± SD was ± 6.31 years (range, years), and most of them (395 [58.26%]) were nulliparous. The number of participants at each gestational age is shown in Table 1. A quadratic regression model was the best description of the predicted mean of the cardiac circumference based on gestational weeks, whereas linear regression was the best-fitted model for predicting the mean based on the biparietal diameter and SD of both independent variables, as presented in Table 2 and Figures 2 and 3. These equations were validated by constructing a z score for each variable. The normalcy of the z scores was evident in a Q-Q plot. The Sharpiro-Wilk W test showed normality in the distribution (P =.58). Additionally, the z scores were evenly distributed above and below 0 across the entire range of gestational ages and biparietal diameters and had a standard normal distribution. The z scores that were outside the range of ±2 SD did not differ significantly from the expected 10% of the values (Figure 4). Percentile models for the cardiac circumference as a function of gestational age in weeks and biparietal diameter in centimeters are shown in Tables 1 and 3, respectively. The z score for each actual cardiac circumference value can be calculated as follows: z score = (measured cardiac circumference value predicted value)/predicted SD. Example of a z score calculation: actual measured biparietal diameter = 4.0 cm; cardiac circumference = 68 mm. Using the formula in Table 2: predicted cardiac circumference = ( ) = mm; predicted SD of cardiac circumference = ( ) = 4.07 mm; and z score = (68 53)/4 = Therefore, the fetuses had an enlarged cardiac circumference at 3.75 SD above the predicted mean cardiac circumference for a fetus whose biparietal diameter was 4 cm (out of the normal range). Discussion Although our cardiac diameter measurement is simple, more practical, reproducible, less time-consuming, and very helpful for early diagnosis of cardiomegaly secondary to various causes, especially fetal anemia, 1 theoretically, the cardiac circumference better represents the fetal heart size than the cardiac diameter. However, in practice, the measurement is more time-consuming and subject to error in cases with a poor cardiac border. Currently, high-resolution sonography allows tracing of the heart perimeter with higher reliability than ever before. Normal reference ranges for the cardiac circumference are very limited, especially z Table 1. Fetal Cardiac Circumference as a Function of Gestational Age GA, Cardiac Circumference, mm wk n 2.5th 5th 10th 50th 90th 95th 97.5th GA indicates gestational age; and n, sample size for each gestational week. J Ultrasound Med 2011; 30:

4 Table 2. Regression Models for Prediction of the Mean and SD of the Fetal Cardiac Circumference Based on Gestational Age and Biparietal Diameter Parameter Model Derived From Regression Analysis r Gestational age (GA), wk Cardiac circumference, mm GA GA SD of cardiac circumference, mm GA 0.28 Biparietal diameter (BPD), cm Cardiac circumference, mm BPD 0.97 SD of cardiac circumference, mm BPD 0.25 Figure 2. Quadratic function relationship between gestational age and the cardiac circumference. The lines represent the 2.5th, 5th, 10th, 50th, 90th, 95th, and 97.5th percentiles. Figure 3. Linear relationship between the biparietal diameter (BPD) and cardiac circumference. The lines represent the 2.5th, 5th, 10th, 50th, 90th, 95th, and 97.5th percentiles. scores for quantitative assessment of fetal cardiac size. On the basis of this study and previous reports, 2,3,5,11 the cardiac size increases steadily through gestational age. However, our results are somewhat different from those of other studies in that the best-fitted model for gestational age was a quadratic function rather than linear, as in other studies. We found that the SD of the cardiac circumference was greater with increasing gestational age. Therefore, we had to analyze and regress the SD separately. To our knowledge, SD analysis was not performed in most previous studies; however, it is critically important for z score assessment. 10,12 In addition to providing z score assessment, another main difference from other studies was that our data were derived from cardio spatiotemporal image correlation. With conventional 2-dimensional sonography, it is difficult to get a proper plane in the 4-chamber view, even with the ultrasound beam exactly perpendicular to the interventricular septum, because the depicted image on the screen, although appearing to be perfect in the x- and y- axes, can be tilted toward or away from the examiner in the Figure 4. Distribution of calculated z scores for the cardiac circumference against gestational age, indicating an adequate level of fit J Ultrasound Med 2011; 30:

5 z-axis, resulting in asymmetry of the left and right sides of the heart and leading to an inaccurate circumference. Obtaining a perfect 4-chamber view is often time-consuming and sometimes impossible. With the innovative cardio spatiotemporal image correlation, this problem has been solved. It is very simple, less time-consuming, and highly reliable for getting the proper orientation. Unlike an examination with 2-dimensional sonography, in which we have to orient the transducer to visualize the proper plane, with the offline analysis of cardio spatiotemporal image correlation, we can control and orient the virtual heart volume to get the proper plane and not have to orient the transducer. The interventricular septum can be simply maneuvered to be on the exact horizontal line in panels A and B, and a total en face view can be displayed in panel C, resulting in more reliable measurements. In this study, we used the area point or area trace function available in 4D View version 9.0 to trace the cardiac outline as meticulously as we wanted. We chose this technique because the heart shape is too complex, not symmetrically geometric, to be accurately assessed with a simple eclipse tool or computed from two diameters, as in previous studies. 5,11 One limitation of the cardio spatiotemporal image correlation used in this study was that the resolution of the volume data sets may have been somewhat compromised in some cases because of fetal movement and maternal breathing. Additionally, even with a high-resolution ultra- Table 3. Fetal Cardiac Circumference as a Function of Biparietal Diameter BPD, Cardiac Circumference, mm BPD, Cardiac Circumference, mm cm 2.5th 5th 10th 50th 90th 95th 97.5th cm 2.5th 5th 10th 50th 90th 95th 97.5th BPD indicates biparietal diameter. J Ultrasound Med 2011; 30:

6 sound machine, the small cardiac structures early in the second trimester could not be clearly distinguished from surrounding structures, and several volume data sets in early gestation were excluded because of unsatisfactory quality for analysis. Moreover, it was sometimes impossible to obtain satisfactory volumes in fetuses with very active and long movement or when they were poorly accessible, especially in a supine position. The strengths of this study included first its large sample size (678), ranging from 15 to 38 examinations per gestational week; constructing a normal reference range with a +1 to 3 SD curve and restricting the SE of the limits of the reference range to 10% of the SD requires a sample size of about 550 fetuses (14 40 weeks). 10 Second, measurement based on offline analysis with cardio spatiotemporal image correlation did not have a time limit, allowing us to obtain reliable planes of exact 4-chamber views. Third, our normative tables included fetuses in early and late gestation, unlike in most previous reports. Finally, z scores for quantitative evaluation were also provided, and the z score distribution against gestational age and biparietal diameter indicated an adequate model fit. In conclusion, reference ranges for the fetal cardiac circumference at each gestational age and biparietal diameter from 14 to 40 weeks were constructed on the basis of cardio spatiotemporal image correlation volume data sets. These reference ranges may be useful tools for assessment of fetal cardiac size, especially when fetal cardiomegaly is suspected. However, the effectiveness of this fetal parameter is yet to be validated by further studies. 7. Chaoui R, Heling KS. New developments in fetal heart scanning: threeand four-dimensional fetal echocardiography. Semin Fetal Neonatal Med 2005; 10: DeVore GR, Polanco B, Sklansky MS, Platt LD. The spin technique: a new method for examination of the fetal outflow tracts using threedimensional ultrasound. Ultrasound Obstet Gynecol 2004; 24: Gonçalves LF, Lee W, Espinoza J, Romero R. Examination of the fetal heart by four-dimensional (4D) ultrasound with spatio-temporal image correlation (STIC). Ultrasound Obstet Gynecol 2006; 27: Royston P, Wright EM. How to construct normal ranges for fetal variables. Ultrasound Obstet Gynecol 1998; 11: Awadh AM, Prefumo F, Bland JM, Carvalho JS. Assessment of the intraobserver variability in the measurement of fetal cardiothoracic ratio using ellipse and diameter methods. Ultrasound Obstet Gynecol 2006; 28: Silverwood RJ, Cole TJ. Statistical methods for constructing gestational age-related reference intervals and centile charts for fetal size. Ultrasound Obstet Gynecol 2007; 29:6 13. References 1. Tongsong T, Wanapirak C, Sirichotiyakul S, Chanprapaph P. Sonographic markers of hemoglobin Bart disease at midpregnancy. J Ultrasound Med 2004; 23: Gembruch U, Shi C, Smrcek JM. Biometry of the fetal heart between 10 and 17 weeks gestation. Fetal Diagn Ther 2000; 15: Guariglia L, Rosati P, Bartolozzi F. Cardiac circumference measurement: possible screening tool in early pregnancy for anomalous cardiac development. Fetal Diagn Ther 2006; 21: Jordaan HV. Cardiac size during prenatal development. Obstet Gynecol 1987; 69: Lee W, Riggs T, Amula V, et al. Fetal echocardiography: z-score reference ranges for a large patient population. Ultrasound Obstet Gynecol 2010; 35: Smrcek JM, Berg C, Geipel A, Fimmers R, Diedrich K, Gembruch U. Early fetal echocardiography: heart biometry and visualization of cardiac structures between 10 and 15 weeks gestation. J Ultrasound Med 2006; 25: J Ultrasound Med 2011; 30: