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Prenatal Detection of Fetal Growth Restriction by Fetal Femur Volume: Efficacy Assessment Using Three-Dimensional Ultrasound
Ultrasound in Med. & Biol., Vol. 33, No. 3, pp. 335–341, 2007 Copyright © 2007 World Federation for Ultrasound in Medicine & Biology Printed in the USA. All rights reserved 0301-5629/07/$–see front matter
doi:10.1016/j.ultrasmedbio.2006.10.013
● Original Contribution PRENATAL DETECTION OF FETAL GROWTH RESTRICTION BY FETAL FEMUR VOLUME: EFFICACY ASSESSMENT USING THREE-DIMENSIONAL ULTRASOUND CHIUNG-HSIN CHANG,* PEI-YING TSAI,* CHEN-HSIANG YU,* HUEI-CHEN KO,† and FONG-MING CHANG* *Department of Obstetrics and Gynecology; and †Research Institute of Behavior Medicine, National Cheng Kung University Medical College, Tainan, Taiwan (Received 1 June 2006; revised 27 September 2006; in final form 5 October 2006)
Abstract—As fetal growth restriction (FGR) may have increased risks with perinatal morbidity and mortality, it is very important to detect FGR prenatally. Fetal femur dysplasia is associated with a variety of congenital syndromes and FGR as well. To date, no prenatal assessment of fetal FV in predicting FGR using threedimensional (3D) ultrasound (US) has been reported. In this study, we used 3D US to test the efficacy of fetal femur volume (FV) measurement in predicting FGR. We calculated the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and efficacy of fetal FV assessed by 3D US in detecting FGR according to the Bayes’ theorem. All the fetuses were singletons and were followed up to delivery to determine whether they were complicated with FGR or not. In total, 304 fetuses without FGR and 42 fetuses with FGR were included for FV assessment in utero by 3D US. Our results showed fetal FV assessed by 3D US can differentiate fetuses with FGR from fetuses without FGR well. The best predicting threshold for FGR is at the 10th percentile of FV. Using the 10th percentile as the cutoff, the sensitivity of fetal FV in predicting FGR was 71.4%, specificity 94.1%, positive predictive value 62.5%, negative predictive value 96.0% and accuracy 91.3%. In addition, fetal FV is superior to fetal biparietal diameter and fetal abdominal circumference in predicting FGR. In conclusion, fetal FV assessed by 3D US can be applied to detect FGR well prenatally. We believe fetal FV assessment by 3D US would be a useful test in detecting fetuses with FGR. (E-mail: fchang@ mail.ncku.edu.tw) © 2007 World Federation for Ultrasound in Medicine & Biology. Key Words: 3D ultrasound, Femur volume, Fetal growth restriction.
Prenatal assessment and evaluation of femur growth is very important because fetal femur dysplasia is associated with FGR (Bromley et al. 1993; Hahmann and Issel 1988; O’Brien and Queenan 1982; Woo et al. 1985). In the past decades, two-dimensional (2D) ultrasound (US) was the most commonly used tool for the measurement of fetal femur length (FL). Besides FL, femur volume (FV) is one of the useful indices in evaluating fetal femur growth, but has never been investigated. However, fetal femur possesses a unique shape and FV cannot be directly assessed by 2D US in utero accurately. After the invention of three-dimensional (3D) US, precise quantitative measurement of fetal organ dimensions becomes possible when the 3D volume is retrieved (Chang FM et al. 1997a; Lee et al. 1994; Merz et al. 1995). Since our first report of primary application of 3D US in obstetrics (Kuo et al. 1992), we have published a series of fetal organ volumetry using 3D US, including
INTRODUCTION Since fetal growth restriction (FGR) may increase the risks of perinatal morbidity and mortality (Lin and Santolaya-Forgas 1998, 1999; Lockwood and Weiner 1986), accurate diagnosis of FGR prenatally offers an opportunity to reduce the complications, such as intrapartum fetal distress, hypoglycemia, hypocalcemia and meconium aspiration pneumonia (Dobson et al. 1981; Lockwood and Weiner 1986; Reed and Droegmueller 1983). These fetuses should be closely monitored and, whenever indicated, promptly delivered, when the diagnosis of FGR is made or suspected on the basis of sonographic findings.
Address correspondence to: Dr. Fong-Ming Chang, Department of Obstetrics and Gynecology, National Cheng Kung University Medical College and Hospital, 138 Victory Road, Tainan, 70428 Taiwan. E-mail: [email protected] 335
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the liver, heart, cerebellum, kidney, adrenal gland, upper arm, thigh, lung, brain as well as humerus volume and we obtained more accurate results than using 2D US (Chang CH et al. 2000, 2002a, 2002b, 2003a, 2003b, 2003c, 2003d, 2003e; Chang FM et al. 1997a, 1997b, 1997c; Liang et al. 1997; Yu et al. 2000). During the past 5 y, we have investigated the use of 3D US in constructing normal fetal growth references as well as in detecting abnormal fetal growth (Chang CH et al. 2000, 2002a, 2002b, 2003a, 2003b, 2003c, 2003d, 2003e, 2005a, 2005b, 2006a, 2006b). To date, no prenatal assessment of fetal FV in predicting FGR using 3D US has been reported. Therefore, in this study, we attempted to use 3D US to test the efficacy of fetal FV measurement in predicting FGR. We calculate the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and efficacy of fetal FV assessed by 3D US in detecting FGR according to the Bayes’ theorem. MATERIALS AND METHODS Patients We performed a prospective and cross-sectional design in this study from January 2004 to December 2004. The patients were examined consecutively without selection. Women who attended the prenatal clinic and were referred for a US examination for fetal biometry were included. All the fetuses enrolled in this study were singletons and the inclusion criteria were as follows: (1) patients with defined last menstrual period (LMP) and confirmed by a dating US examination in early pregnancy, either by crown-rump length (CRL) or biparietal diameter (BPD); and (2) pregnancies with gestational age (GA) ranging from 20 to 40 weeks of gestation. The setting was performed at the Ultrasound Unit of the Department of Obstetrics and Gynecology, National Cheng Kung University Hospital. All the pregnant women gave their informed consents and this study was approved by the Institutional Review Board of National Cheng Kung University Hospital. Antenatal assessment of FV by 3D ultrasound The 3D US equipment (Voluson 530D, Kretz, Zipf, Austria) with a 3.0 to 5.0 MHz transabdominal mechanical transducer (S-VAW 3 to 5) was used for fetal FV scanning in each fetus. The details of 3D US in scanning and assessing fetal organ volumes have been previously described elsewhere (Chang CH et al. 2003e). In brief, a high-resolution, real-time 2D US scanner was used for scanning the traditional plane of fetal femur bone. Then, we turned on the 3D transabdominal Voluson transducer to measure fetal FV with the normal velocity mode (which swept 60 to 90° automatically within 4 s) when the fetus was at rest.
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Fig. 1. Stepwise measurements of fetal femur volume by 3D ultrasound. We initially used the traditional plane for measuring the femur length on the first screen (upper left panel) and rotated this plane to make the femur in a horizontal position. Then we fixed this plane as the basis and moved the cursor along the axis of the femur from one end of the diaphysis to the other end, slice by slice every 3 mm. The corresponding transaxial plane was simultaneously illustrated on the second screen (upper right panel) and the dot cursor was marked along the outline of the femur. The dotted area in the upper-right panel was measured and the thickness of each slice by a built-in computer as we proceeded along the axis of the femur. Meanwhile, the image of the third plane was displayed (lower left panel) and the movement of the measured plane was displayed simultaneously (lower right panel). The integration of the femur volume was calculated by the 3D US automatically when the cursor was moved forward and the area was enclosed.
Figure 1 shows the stepwise measurements of FV by 3D US and as described below. At first, we used the traditional plane of fetal femur for measuring the FL on the first screen (upper left panel) and rotated this plane to make the femur in a horizontal position. Then, we fixed this plane as the basis and moved the cursor along the axis of the femur from one end of the diaphysis to the other end, slice-by-slice every 3 mm. The corresponding transaxial plane was simultaneously illustrated on the second screen (upper right panel) and the dot cursor was marked along the outline of the femur. The dotted area in the upper-right panel was measured and the thickness of each slice by a built-in computer as we proceeded along the axis of the femur. Meanwhile, the image of the third plane was displayed (lower left panel) and the movement of the measured plane was displayed simultaneously (lower right panel). The integration of FV was calculated by the 3D US automatically when the cursor was moved forward and the area was enclosed. The built-in 3D-view software allows the 3D volume to display simultaneously in three perpendicular orthogonal planes on the monitor. The data set was
Predicting FGR by fetal femur volume ● C-H. CHANG et al.
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Fig. 2. The scattergram of fetal femur volume vs. gestational age (GA) in two groups; fetuses with fetal growth restriction (FGR) (black triangle dot) and fetuses without FGR (white circle dot).
further saved into the built-in computer or in the laser disks for further retrieval and processing, such as volume determination or 3D-image reconstruction. Diagnosis of FGR All the fetuses were scanned once only and all were followed up to delivery to determine whether they were born with FGR or without FGR. When their birth weights were below the 10th percentile for GA according to the Taiwanese standard (Hsieh et al. 1991), they were classified as fetuses with FGR; when their birth weights were above or equal to the 10th percentile for GA according to the Taiwanese standard, they were grouped as fetuses without FGR.
from a normal population as different screening thresholds. The statistical efficacy of each threshold of FV was computed and a receiver operating characteristic (ROC) curve was constructed to determine the optimal threshold. In addition, we compared the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and accuracy according to the Bayes’ theorem between the non-FGR and FGR fetuses. Furthermore, we also compared the sensitivity, specificity and ROC curves among fetal FV, fetal BPD and fetal abdominal circumference (AC) in predicting the efficacy of FGR. RESULTS
Statistics All the data of fetal FV measurements and relevant clinical indices (such as gender, birth weight etc.) were put into an IBM-compatible personal computer for final analysis. We used the SPSS-PC statistical package (Chicago, Illinois, USA) to perform statistical calculation. Linear regression analysis and correlation analysis were calculated to test the relationship between the independent and dependent variables. Polynomial regression analysis was calculated from the first-order to the fourthorder to find the best-fit equations. To obtain the predicted values of the FV using GA as the independent variables (Chitty et al. 1994a, 1994b, 1994c), we further generated a table from the best-fit equation. A p-value of less than 0.05 was considered to be statistically-significant. We used our centile values of fetal FV obtained
Totally, 304 fetuses without FGR and 42 fetuses with FGR were included for final analysis. The maternal ages were ranged between 23 and 39 y for the FGR group and were ranged between 16 and 42 y for the non-FGR group. The scattergram of fetal FV versus GA is displayed in Fig. 2. The fetal FV in FGR fetuses is significantly smaller than that in non-FGR fetuses (p ⬍ 0.001). In the group of 304 fetuses without FGR, using GA as the independent variable and fetal FV as the dependent variable, the best-fit equation of fetal FV is a secondorder polynomial regression equation: FV (ml) ⫽ 0.0056 GA2 ⫺ 0.1024 GA ⫹ 0.8276 (r ⫽ 0.97, n ⫽ 304, p ⬍ 0.0001), with SD of fetal FV (ml) ⫽ 1.2533 (⫺0.11333 ⫹ 0.0127 GA). The predicted values of the normal growth centiles of fetal FV were calculated by this equation and are listed in Table 1.
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Table 1. Predicted values of fetal femur volume by 3D ultrasound Femur volume (mL) GA
10th
25th
50th
75th
90th
SD
20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40
0.79 0.90 1.02 1.15 1.29 1.44 1.60 1.78 1.96 2.16 2.37 2.59 2.82 3.06 3.31 3.57 3.85 4.13 4.43 4.74 5.06
0.90 1.02 1.14 1.28 1.43 1.59 1.77 1.95 2.15 2.35 2.57 2.80 3.04 3.29 3.55 3.82 4.11 4.40 4.71 5.03 5.36
1.02 1.15 1.29 1.43 1.60 1.77 1.95 2.15 2.35 2.57 2.80 3.03 3.29 3.55 3.82 4.10 4.40 4.71 5.02 5.35 5.69
1.14 1.28 1.43 1.59 1.76 1.94 2.13 2.34 2.56 2.78 3.02 3.27 3.53 3.81 4.09 4.38 4.69 5.01 5.34 5.67 6.03
1.25 1.39 1.55 1.72 1.90 2.10 2.30 2.51 2.74 2.98 3.23 3.48 3.76 4.04 4.33 4.63 4.95 5.28 5.62 5.96 6.32
0.18 0.19 0.21 0.22 0.24 0.26 0.27 0.29 0.30 0.32 0.34 0.35 0.37 0.38 0.40 0.42 0.43 0.45 0.46 0.48 0.49
GA ⫽ gestational age (weeks).
Using the different FV centile values from normal fetuses in this study as screening thresholds, the efficacy of different thresholds of FV by 3D US in predicting FGR is shown in Table 2. From the results in Table 2, we constructed an ROC curve (Fig. 3). The optimal operating slope for the ROC curve corresponded to a FV threshold of the 10th percentile, with sensitivity 71.4%, specificity 94.1%, positive predictive value 62.5%, negative predictive value 96.0% and accuracy 91.3%, respectively. In addition, we also compared the sensitivity, specificity and ROC curves among fetal FV, fetal BPD and AC. The results are also depicted in Fig. 3, which illustrates that fetal FV is superior to fetal BPD and AC in predicting FGR. In this study, all the measurements of fetal FV were undertaken by one operator (CHC) and no interobserver error needs to be considered. The reproducibility data for determining the intraobserver error of fetal FV were assessed by repeated measurements on 20 non-FGR fetuses with 20 to 40 weeks of gestation by the same operator (CHC). As demonstrated in Fig. 4, our result showed that the correlation coefficient of intraobserver errors was highly significant (r ⫽ 0.99, n ⫽ 20, p ⬍ 0.0001). In addition, there was no statistical difference of intraobserver error as examined by a paired t-test. DISCUSSION Skeletal abnormalities are relatively common, with an incidence of 1/500 births (McHugo 2000). Fetal femur
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dysplasia may be indicative of a syndrome, a chromosomal aberration or even a possibility of FGR (Benacerraf et al. 1987; Bromley et al. 1993; Hahmann and Issel 1988; LaFollette et al. 1989; Nyberg et al. 1993; O’Brien and Queenan 1982; Woo et al. 1985). Thus, we postulate that fetal femur growth may allow early prenatal diagnosis and appropriate management of these fetuses as soon as possible. From our study, we prove this hypothesis. Nevertheless, it is nearly impossible accurately to assess fetal FV prenatally by 2D US. This is for the reason that, using 2D US, the volumetry of most fetal organs has to depend upon the assumption that fetal organs observe an ideal geometric shape, which may be erroneous (Jeanty et al. 1985). With the advent of 3D US, a series of precise quantitative measurements of fetal organ volumes have been reported, e.g., heart volume (Chang FM et al. 1997a), lung volume (Chang CH et al. 2003b; Lee et al. 1996), liver volume (Chang CH et al. 2003c; Chang FM et al. 1997b; Laudy et al. 1998), brain volume (Chang CH et al. 2003d; Endres and Cohen 2001), cerebellar volume (Chang CH et al. 2000), renal volume (Yu et al. 2000), upper arm volume (Chang CH et al. 2002a) and thigh volume (Chang CH et al. 2003a). In the evaluation of fetal skeletal volume, several papers using 3D US for the assessment of the volume of fetal lumbar spine and the spinal canal have been published (Schild et al. 1999, 2000; Wallny et al. 1999). However, no reports for the assessment of normal fetal FV and the prediction of FGR using 3D US have been published to date. This study may be the first series in reporting the assessment of fetal FV using 3D US in predicting FGR. According to the previous report, the qualitative 3D US rendering reconstruction can assist in the diagnosis of skeletal dysplasias because it offers the potential better to understand spatial relationships of normal and abnormal fetal anatomy than conventional 2D US (Garjian et al. 2000). In addition to the qualitative 3D US by other investigators (Garjian et al. 2000), our study demonstrates that quantitative 3D US can also allow direct assessment of fetal FV in assisting the prenatal diagnosis of femur dysplasia.
Table 2. Efficacy of different percentiles of fetal femur volume in predicting fetal growth restriction Percentile
Sen (%)
Spe (%)
PPV (%)
NPV (%)
Acc (%)
5th 10th 25th 50th
35.7 71.4 95.3 100
95.4 94.1 78.0 59.2
51.7 62.5 37.4 25.3
91.5 96.0 99.2 100
88.2 91.3 80.1 64.2
Sen ⫽ sensitivity; Spe ⫽ specificity; PPV ⫽ positive predictive value; NPV ⫽ negative predictive value; Acc ⫽ accuracy.
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Fig. 3. Receiver operating characteristic (ROC) curves for the prediction of fetal growth restriction (FGR) among femur volume (FV), biparietal diameter (BPD) and abdominal circumference (AC). Data points are the measured values of each of the various fetal biometries. The best predicting threshold for FGR is at the 10th percentile of FV (arrow). The fetal FV is superior to fetal BPD and AC in predicting FGR.
For the prenatal diagnosis of FGR, we have analyzed testing thresholds of FV obtained from normal fetuses. From the results of Table 1 and Fig. 3, the best cutoff criterion of fetal FV in predicting FGR is the threshold of the 10th percentile. Using the 10th percentile of FV as the cutoff criterion, the results turned out to be satisfactory, with sensitivity 71.4%, specificity 94.1%,
positive predictive value 62.5%, negative predictive value 96.0% and accuracy 91.3%, respectively. These results indicated that the efficacy of FV in predicting FGR using 3D US prenatally is suitable in clinical practice. For the reproducibility of FV using 3D US, all the measurements in this study were performed by the same
Fig. 4. The assessment of intraobserver reproducibility of fetal femur volume using 3D ultrasound.
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operator (CHC) and the consideration about the interobserver error was not necessary. For the intraobserver error in this study (Fig. 4), our result showed it was highly significant between the repeated measurements of fetal FV by 3D US (r ⫽ 0.99, p ⬍ 0.0001). Our study implied that using 3D US to assess fetal FV is clinically applicable, with a highly significant reproducibility in repeated measurements. In conclusion, 3D US-assessed fetal FV can be applied in evaluating normal fetal FV and in predicting FGR in utero. We believe that fetal FV assessment using 3D US may be added to the daily practice of prenatal ultrasound scanning in predicting and monitoring the fetuses with FGR. Acknowledgments—This study was supported in part by grants to FMC and to CHC from the National Science Council, Taipei, Taiwan. In addition, this study was also supported in part by a grant from the Foundation of Premature Babies, Taipei, Taiwan, and the Foundation of Behavior and Maternal-Children Health, Tainan, Taiwan. The authors are grateful to Ms. Chi-Ling Chen, Ms. Yueh-Chin Cheng and Ms. Yi-Jen Wang for their assistance.
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Volume 33, Number 3, 2007 sional ultrasound: Efficacy evaluation. Ultrasound Med Biol 2006a;32:13–17. Chang CH, Yu CH, Ko HC, Chen CL, Chang FM. Predicting fetal growth restriction by humerus volume: A three-dimensional ultrasound study. Ultrasound Med Biol 2006b;32:791–795. Chang FM, Hsu KF, Ko HC, et al. The fetal heart volume assessment by three-dimensional ultrasound. Ultrasound Obstet Gynecol 1997a;9:42– 48. Chang FM, Hsu KF, Ko HC, et al. Three dimensional ultrasound assessment of the fetal liver volume in normal pregnancy: A comparison of reproducibility with two-dimensional ultrasound and a search for a volume constant. Ultrasound Med Biol 1997b;23:381– 389. Chang FM, Liang RI, Ko HC, Chang CH, Yu CH. Three-dimensional ultrasound-assessed the fetal thigh volumetry in predicting birth weight. Obstet Gynecol 1997c;90:331–339. Chitty LS, Altman DG, Henderson A, et al. Charts of the fetal size: 2. Head measurements. Br J Obstet Gynaecol 1994a;101:35– 43. Chitty LS, Altman DG, Henderson A, et al. Charts of the fetal size: 3. Abdominal measurements. Br J Obstet Gynaecol 1994b;101:125– 131. Chitty LS, Altman DG, Henderson A, et al. Charts of the fetal size: 4. Femur length. Br J Obstet Gynaecol 1994c;101:132–135. Dobson PC, Abell DA, Beischer NA. Mortality and morbidity of fetal growth retardation. Aust N Z J Obstet Gynaecol 1981;21:69 –72. Endres LK, Cohen L. Reliability and validity of three-dimensional the fetal brain volumes. J Ultrasound Med 2001;20:1265–1269. Garjian KV, Pretorius DH, Budorick NE, Cantrell CJ, Johnson DD, Nelson TR. Fetal skeletal dysplasia: Three-dimensional US—initial experience. Radiology 2000;214:717–723. Hahmann K, Issel EP. Assessment of fetal growth using the humerus and femur in ultrasound fetometry. Zentralbl Gynakol 1988;110: 370 –382. Hsieh TT, Hsu JJ, Chen CJ, Chiu TH, Liou JD, Hsieh CC, Lo LM, Kuo DM, Soong YK. Analysis of birth weight and gestational age in Taiwan. J Formosan Med Assoc 1991;90:382–387. Jeanty P, Romero R, Hobbins JC. Fetal limb volume: A new parameter to assess fetal growth and nutrition. J Ultrasound Med 1985;4:273–282. Kuo HC, Chang FM, Wu CH, Yao BL, Liu CH. The primary application of three-dimensional ultrasonography in obstetrics. Am J Obstet Gynecol 1992;166:880 – 886. LaFollette L, Filly RA, Anderson R, Golbus MS. Fetal femur length to detect trisomy 21. J Ultrasound Med 1989;8:657– 660. Laudy JA, Janssen MM, Stuyk PC, Stijnen T, Wallenburg HC, Wladimiroff JW. The fetal liver volume measurement by three-dimensional ultrasonography: A preliminary study. Ultrasound Obstet Gynecol 1998;12:93–96. Lee A, Deutinger J, Bernaschek G. Voluvision: Three-dimensional ultrasonography of the fetal malformations. Am J Obstet Gynecol 1994;170:1312–1314. Lee A, Kratochwil A, Stumpflen I, Deutinger J, Bernaschek G. The fetal lung volume determination by three-dimensional ultrasonography. Am J Obstet Gynecol 1996;175:588 –592. Liang RI, Chang FM, Yao BL, Chang CH, Yu CH, Ko HC. Predicting birth weight by the fetal upper-arm volume with use of three-dimensional ultrasonography. Am J Obstet Gynecol 1997;177:632– 638. Lin CC, Santolaya-Forgas J. Current concepts of fetal growth restriction: Part I. Causes, classification, and pathophysiology. Obstet Gynecol 1998;92:1044 –1055. Lin CC, Santolaya-Forgas J. Current concepts of fetal growth restriction: Part II. Diagnosis and management. Obstet Gynecol 1999;93: 140 –146. Lockwood CJ, Weiner S. Assessment of fetal growth. Clin Perinatol 1986;13:3–35. McHugo JM. Skeletal abnormalities. In: Twining P, McHugo JM, Pilling DW, eds. Textbook of fetal abnormalities. London, UK: Churchill Livingstone, 2000:238 –240. Merz E, Bahlmann F, Weber G. Volume scanning in the evaluation of the fetal malformations: A new dimension in prenatal diagnosis. Ultrasound Obstet Gynecol 1995;5:222–227.
Predicting FGR by fetal femur volume ● C-H. CHANG et al. Nyberg DA, Resta RG, Luthy DA, Hickok DE, Williams MA. Humerus and femur length shortening in the detection of Down syndrome. Am J Obstet Gynecol 1993;168:534 –538. O’Brien GD, Queenan JT. Ultrasound fetal femur length in relation to intrauterine growth retardation. Part II. Am J Obstet Gynecol 1982; 144:35–39. Reed K, Droegmueller W. Intrauterine growth retardation. In: Cetrulo CL, Sbarra AJ eds. The problem-oriented medical record for highrisk obstetrics. New York: Plenum Medical, 1983:175. Schild RL, Wallny T, Fimmers R, Hansmann M. Fetal lumbar spine volumetry by three-dimensional ultrasound. Ultrasound Obstet Gynecol 1999;13:335–339.
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doi:10.1016/j.ultrasmedbio.2006.10.013
● Original Contribution PRENATAL DETECTION OF FETAL GROWTH RESTRICTION BY FETAL FEMUR VOLUME: EFFICACY ASSESSMENT USING THREE-DIMENSIONAL ULTRASOUND CHIUNG-HSIN CHANG,* PEI-YING TSAI,* CHEN-HSIANG YU,* HUEI-CHEN KO,† and FONG-MING CHANG* *Department of Obstetrics and Gynecology; and †Research Institute of Behavior Medicine, National Cheng Kung University Medical College, Tainan, Taiwan (Received 1 June 2006; revised 27 September 2006; in final form 5 October 2006)
Abstract—As fetal growth restriction (FGR) may have increased risks with perinatal morbidity and mortality, it is very important to detect FGR prenatally. Fetal femur dysplasia is associated with a variety of congenital syndromes and FGR as well. To date, no prenatal assessment of fetal FV in predicting FGR using threedimensional (3D) ultrasound (US) has been reported. In this study, we used 3D US to test the efficacy of fetal femur volume (FV) measurement in predicting FGR. We calculated the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and efficacy of fetal FV assessed by 3D US in detecting FGR according to the Bayes’ theorem. All the fetuses were singletons and were followed up to delivery to determine whether they were complicated with FGR or not. In total, 304 fetuses without FGR and 42 fetuses with FGR were included for FV assessment in utero by 3D US. Our results showed fetal FV assessed by 3D US can differentiate fetuses with FGR from fetuses without FGR well. The best predicting threshold for FGR is at the 10th percentile of FV. Using the 10th percentile as the cutoff, the sensitivity of fetal FV in predicting FGR was 71.4%, specificity 94.1%, positive predictive value 62.5%, negative predictive value 96.0% and accuracy 91.3%. In addition, fetal FV is superior to fetal biparietal diameter and fetal abdominal circumference in predicting FGR. In conclusion, fetal FV assessed by 3D US can be applied to detect FGR well prenatally. We believe fetal FV assessment by 3D US would be a useful test in detecting fetuses with FGR. (E-mail: fchang@ mail.ncku.edu.tw) © 2007 World Federation for Ultrasound in Medicine & Biology. Key Words: 3D ultrasound, Femur volume, Fetal growth restriction.
Prenatal assessment and evaluation of femur growth is very important because fetal femur dysplasia is associated with FGR (Bromley et al. 1993; Hahmann and Issel 1988; O’Brien and Queenan 1982; Woo et al. 1985). In the past decades, two-dimensional (2D) ultrasound (US) was the most commonly used tool for the measurement of fetal femur length (FL). Besides FL, femur volume (FV) is one of the useful indices in evaluating fetal femur growth, but has never been investigated. However, fetal femur possesses a unique shape and FV cannot be directly assessed by 2D US in utero accurately. After the invention of three-dimensional (3D) US, precise quantitative measurement of fetal organ dimensions becomes possible when the 3D volume is retrieved (Chang FM et al. 1997a; Lee et al. 1994; Merz et al. 1995). Since our first report of primary application of 3D US in obstetrics (Kuo et al. 1992), we have published a series of fetal organ volumetry using 3D US, including
INTRODUCTION Since fetal growth restriction (FGR) may increase the risks of perinatal morbidity and mortality (Lin and Santolaya-Forgas 1998, 1999; Lockwood and Weiner 1986), accurate diagnosis of FGR prenatally offers an opportunity to reduce the complications, such as intrapartum fetal distress, hypoglycemia, hypocalcemia and meconium aspiration pneumonia (Dobson et al. 1981; Lockwood and Weiner 1986; Reed and Droegmueller 1983). These fetuses should be closely monitored and, whenever indicated, promptly delivered, when the diagnosis of FGR is made or suspected on the basis of sonographic findings.
Address correspondence to: Dr. Fong-Ming Chang, Department of Obstetrics and Gynecology, National Cheng Kung University Medical College and Hospital, 138 Victory Road, Tainan, 70428 Taiwan. E-mail: [email protected] 335
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the liver, heart, cerebellum, kidney, adrenal gland, upper arm, thigh, lung, brain as well as humerus volume and we obtained more accurate results than using 2D US (Chang CH et al. 2000, 2002a, 2002b, 2003a, 2003b, 2003c, 2003d, 2003e; Chang FM et al. 1997a, 1997b, 1997c; Liang et al. 1997; Yu et al. 2000). During the past 5 y, we have investigated the use of 3D US in constructing normal fetal growth references as well as in detecting abnormal fetal growth (Chang CH et al. 2000, 2002a, 2002b, 2003a, 2003b, 2003c, 2003d, 2003e, 2005a, 2005b, 2006a, 2006b). To date, no prenatal assessment of fetal FV in predicting FGR using 3D US has been reported. Therefore, in this study, we attempted to use 3D US to test the efficacy of fetal FV measurement in predicting FGR. We calculate the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and efficacy of fetal FV assessed by 3D US in detecting FGR according to the Bayes’ theorem. MATERIALS AND METHODS Patients We performed a prospective and cross-sectional design in this study from January 2004 to December 2004. The patients were examined consecutively without selection. Women who attended the prenatal clinic and were referred for a US examination for fetal biometry were included. All the fetuses enrolled in this study were singletons and the inclusion criteria were as follows: (1) patients with defined last menstrual period (LMP) and confirmed by a dating US examination in early pregnancy, either by crown-rump length (CRL) or biparietal diameter (BPD); and (2) pregnancies with gestational age (GA) ranging from 20 to 40 weeks of gestation. The setting was performed at the Ultrasound Unit of the Department of Obstetrics and Gynecology, National Cheng Kung University Hospital. All the pregnant women gave their informed consents and this study was approved by the Institutional Review Board of National Cheng Kung University Hospital. Antenatal assessment of FV by 3D ultrasound The 3D US equipment (Voluson 530D, Kretz, Zipf, Austria) with a 3.0 to 5.0 MHz transabdominal mechanical transducer (S-VAW 3 to 5) was used for fetal FV scanning in each fetus. The details of 3D US in scanning and assessing fetal organ volumes have been previously described elsewhere (Chang CH et al. 2003e). In brief, a high-resolution, real-time 2D US scanner was used for scanning the traditional plane of fetal femur bone. Then, we turned on the 3D transabdominal Voluson transducer to measure fetal FV with the normal velocity mode (which swept 60 to 90° automatically within 4 s) when the fetus was at rest.
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Fig. 1. Stepwise measurements of fetal femur volume by 3D ultrasound. We initially used the traditional plane for measuring the femur length on the first screen (upper left panel) and rotated this plane to make the femur in a horizontal position. Then we fixed this plane as the basis and moved the cursor along the axis of the femur from one end of the diaphysis to the other end, slice by slice every 3 mm. The corresponding transaxial plane was simultaneously illustrated on the second screen (upper right panel) and the dot cursor was marked along the outline of the femur. The dotted area in the upper-right panel was measured and the thickness of each slice by a built-in computer as we proceeded along the axis of the femur. Meanwhile, the image of the third plane was displayed (lower left panel) and the movement of the measured plane was displayed simultaneously (lower right panel). The integration of the femur volume was calculated by the 3D US automatically when the cursor was moved forward and the area was enclosed.
Figure 1 shows the stepwise measurements of FV by 3D US and as described below. At first, we used the traditional plane of fetal femur for measuring the FL on the first screen (upper left panel) and rotated this plane to make the femur in a horizontal position. Then, we fixed this plane as the basis and moved the cursor along the axis of the femur from one end of the diaphysis to the other end, slice-by-slice every 3 mm. The corresponding transaxial plane was simultaneously illustrated on the second screen (upper right panel) and the dot cursor was marked along the outline of the femur. The dotted area in the upper-right panel was measured and the thickness of each slice by a built-in computer as we proceeded along the axis of the femur. Meanwhile, the image of the third plane was displayed (lower left panel) and the movement of the measured plane was displayed simultaneously (lower right panel). The integration of FV was calculated by the 3D US automatically when the cursor was moved forward and the area was enclosed. The built-in 3D-view software allows the 3D volume to display simultaneously in three perpendicular orthogonal planes on the monitor. The data set was
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Fig. 2. The scattergram of fetal femur volume vs. gestational age (GA) in two groups; fetuses with fetal growth restriction (FGR) (black triangle dot) and fetuses without FGR (white circle dot).
further saved into the built-in computer or in the laser disks for further retrieval and processing, such as volume determination or 3D-image reconstruction. Diagnosis of FGR All the fetuses were scanned once only and all were followed up to delivery to determine whether they were born with FGR or without FGR. When their birth weights were below the 10th percentile for GA according to the Taiwanese standard (Hsieh et al. 1991), they were classified as fetuses with FGR; when their birth weights were above or equal to the 10th percentile for GA according to the Taiwanese standard, they were grouped as fetuses without FGR.
from a normal population as different screening thresholds. The statistical efficacy of each threshold of FV was computed and a receiver operating characteristic (ROC) curve was constructed to determine the optimal threshold. In addition, we compared the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and accuracy according to the Bayes’ theorem between the non-FGR and FGR fetuses. Furthermore, we also compared the sensitivity, specificity and ROC curves among fetal FV, fetal BPD and fetal abdominal circumference (AC) in predicting the efficacy of FGR. RESULTS
Statistics All the data of fetal FV measurements and relevant clinical indices (such as gender, birth weight etc.) were put into an IBM-compatible personal computer for final analysis. We used the SPSS-PC statistical package (Chicago, Illinois, USA) to perform statistical calculation. Linear regression analysis and correlation analysis were calculated to test the relationship between the independent and dependent variables. Polynomial regression analysis was calculated from the first-order to the fourthorder to find the best-fit equations. To obtain the predicted values of the FV using GA as the independent variables (Chitty et al. 1994a, 1994b, 1994c), we further generated a table from the best-fit equation. A p-value of less than 0.05 was considered to be statistically-significant. We used our centile values of fetal FV obtained
Totally, 304 fetuses without FGR and 42 fetuses with FGR were included for final analysis. The maternal ages were ranged between 23 and 39 y for the FGR group and were ranged between 16 and 42 y for the non-FGR group. The scattergram of fetal FV versus GA is displayed in Fig. 2. The fetal FV in FGR fetuses is significantly smaller than that in non-FGR fetuses (p ⬍ 0.001). In the group of 304 fetuses without FGR, using GA as the independent variable and fetal FV as the dependent variable, the best-fit equation of fetal FV is a secondorder polynomial regression equation: FV (ml) ⫽ 0.0056 GA2 ⫺ 0.1024 GA ⫹ 0.8276 (r ⫽ 0.97, n ⫽ 304, p ⬍ 0.0001), with SD of fetal FV (ml) ⫽ 1.2533 (⫺0.11333 ⫹ 0.0127 GA). The predicted values of the normal growth centiles of fetal FV were calculated by this equation and are listed in Table 1.
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Table 1. Predicted values of fetal femur volume by 3D ultrasound Femur volume (mL) GA
10th
25th
50th
75th
90th
SD
20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40
0.79 0.90 1.02 1.15 1.29 1.44 1.60 1.78 1.96 2.16 2.37 2.59 2.82 3.06 3.31 3.57 3.85 4.13 4.43 4.74 5.06
0.90 1.02 1.14 1.28 1.43 1.59 1.77 1.95 2.15 2.35 2.57 2.80 3.04 3.29 3.55 3.82 4.11 4.40 4.71 5.03 5.36
1.02 1.15 1.29 1.43 1.60 1.77 1.95 2.15 2.35 2.57 2.80 3.03 3.29 3.55 3.82 4.10 4.40 4.71 5.02 5.35 5.69
1.14 1.28 1.43 1.59 1.76 1.94 2.13 2.34 2.56 2.78 3.02 3.27 3.53 3.81 4.09 4.38 4.69 5.01 5.34 5.67 6.03
1.25 1.39 1.55 1.72 1.90 2.10 2.30 2.51 2.74 2.98 3.23 3.48 3.76 4.04 4.33 4.63 4.95 5.28 5.62 5.96 6.32
0.18 0.19 0.21 0.22 0.24 0.26 0.27 0.29 0.30 0.32 0.34 0.35 0.37 0.38 0.40 0.42 0.43 0.45 0.46 0.48 0.49
GA ⫽ gestational age (weeks).
Using the different FV centile values from normal fetuses in this study as screening thresholds, the efficacy of different thresholds of FV by 3D US in predicting FGR is shown in Table 2. From the results in Table 2, we constructed an ROC curve (Fig. 3). The optimal operating slope for the ROC curve corresponded to a FV threshold of the 10th percentile, with sensitivity 71.4%, specificity 94.1%, positive predictive value 62.5%, negative predictive value 96.0% and accuracy 91.3%, respectively. In addition, we also compared the sensitivity, specificity and ROC curves among fetal FV, fetal BPD and AC. The results are also depicted in Fig. 3, which illustrates that fetal FV is superior to fetal BPD and AC in predicting FGR. In this study, all the measurements of fetal FV were undertaken by one operator (CHC) and no interobserver error needs to be considered. The reproducibility data for determining the intraobserver error of fetal FV were assessed by repeated measurements on 20 non-FGR fetuses with 20 to 40 weeks of gestation by the same operator (CHC). As demonstrated in Fig. 4, our result showed that the correlation coefficient of intraobserver errors was highly significant (r ⫽ 0.99, n ⫽ 20, p ⬍ 0.0001). In addition, there was no statistical difference of intraobserver error as examined by a paired t-test. DISCUSSION Skeletal abnormalities are relatively common, with an incidence of 1/500 births (McHugo 2000). Fetal femur
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dysplasia may be indicative of a syndrome, a chromosomal aberration or even a possibility of FGR (Benacerraf et al. 1987; Bromley et al. 1993; Hahmann and Issel 1988; LaFollette et al. 1989; Nyberg et al. 1993; O’Brien and Queenan 1982; Woo et al. 1985). Thus, we postulate that fetal femur growth may allow early prenatal diagnosis and appropriate management of these fetuses as soon as possible. From our study, we prove this hypothesis. Nevertheless, it is nearly impossible accurately to assess fetal FV prenatally by 2D US. This is for the reason that, using 2D US, the volumetry of most fetal organs has to depend upon the assumption that fetal organs observe an ideal geometric shape, which may be erroneous (Jeanty et al. 1985). With the advent of 3D US, a series of precise quantitative measurements of fetal organ volumes have been reported, e.g., heart volume (Chang FM et al. 1997a), lung volume (Chang CH et al. 2003b; Lee et al. 1996), liver volume (Chang CH et al. 2003c; Chang FM et al. 1997b; Laudy et al. 1998), brain volume (Chang CH et al. 2003d; Endres and Cohen 2001), cerebellar volume (Chang CH et al. 2000), renal volume (Yu et al. 2000), upper arm volume (Chang CH et al. 2002a) and thigh volume (Chang CH et al. 2003a). In the evaluation of fetal skeletal volume, several papers using 3D US for the assessment of the volume of fetal lumbar spine and the spinal canal have been published (Schild et al. 1999, 2000; Wallny et al. 1999). However, no reports for the assessment of normal fetal FV and the prediction of FGR using 3D US have been published to date. This study may be the first series in reporting the assessment of fetal FV using 3D US in predicting FGR. According to the previous report, the qualitative 3D US rendering reconstruction can assist in the diagnosis of skeletal dysplasias because it offers the potential better to understand spatial relationships of normal and abnormal fetal anatomy than conventional 2D US (Garjian et al. 2000). In addition to the qualitative 3D US by other investigators (Garjian et al. 2000), our study demonstrates that quantitative 3D US can also allow direct assessment of fetal FV in assisting the prenatal diagnosis of femur dysplasia.
Table 2. Efficacy of different percentiles of fetal femur volume in predicting fetal growth restriction Percentile
Sen (%)
Spe (%)
PPV (%)
NPV (%)
Acc (%)
5th 10th 25th 50th
35.7 71.4 95.3 100
95.4 94.1 78.0 59.2
51.7 62.5 37.4 25.3
91.5 96.0 99.2 100
88.2 91.3 80.1 64.2
Sen ⫽ sensitivity; Spe ⫽ specificity; PPV ⫽ positive predictive value; NPV ⫽ negative predictive value; Acc ⫽ accuracy.
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Fig. 3. Receiver operating characteristic (ROC) curves for the prediction of fetal growth restriction (FGR) among femur volume (FV), biparietal diameter (BPD) and abdominal circumference (AC). Data points are the measured values of each of the various fetal biometries. The best predicting threshold for FGR is at the 10th percentile of FV (arrow). The fetal FV is superior to fetal BPD and AC in predicting FGR.
For the prenatal diagnosis of FGR, we have analyzed testing thresholds of FV obtained from normal fetuses. From the results of Table 1 and Fig. 3, the best cutoff criterion of fetal FV in predicting FGR is the threshold of the 10th percentile. Using the 10th percentile of FV as the cutoff criterion, the results turned out to be satisfactory, with sensitivity 71.4%, specificity 94.1%,
positive predictive value 62.5%, negative predictive value 96.0% and accuracy 91.3%, respectively. These results indicated that the efficacy of FV in predicting FGR using 3D US prenatally is suitable in clinical practice. For the reproducibility of FV using 3D US, all the measurements in this study were performed by the same
Fig. 4. The assessment of intraobserver reproducibility of fetal femur volume using 3D ultrasound.
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operator (CHC) and the consideration about the interobserver error was not necessary. For the intraobserver error in this study (Fig. 4), our result showed it was highly significant between the repeated measurements of fetal FV by 3D US (r ⫽ 0.99, p ⬍ 0.0001). Our study implied that using 3D US to assess fetal FV is clinically applicable, with a highly significant reproducibility in repeated measurements. In conclusion, 3D US-assessed fetal FV can be applied in evaluating normal fetal FV and in predicting FGR in utero. We believe that fetal FV assessment using 3D US may be added to the daily practice of prenatal ultrasound scanning in predicting and monitoring the fetuses with FGR. Acknowledgments—This study was supported in part by grants to FMC and to CHC from the National Science Council, Taipei, Taiwan. In addition, this study was also supported in part by a grant from the Foundation of Premature Babies, Taipei, Taiwan, and the Foundation of Behavior and Maternal-Children Health, Tainan, Taiwan. The authors are grateful to Ms. Chi-Ling Chen, Ms. Yueh-Chin Cheng and Ms. Yi-Jen Wang for their assistance.
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