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ORIGINAL RESEARCH
Reference Ranges for the Pulsatility Index of the Fetal Aortic Isthmus in Singleton and Twin Pregnancies Francisco Gámez, MD, PhD, María José Rodríguez, MD, PhD, José María Tenías, MD, PhD, Javier García, MD, Pilar Pintado, MD, PhD, Raquel Martín, MD, Ricardo Pérez, MD, PhD, Luis Ortiz-Quintana, MD, PhD, Juan De León-Luis, MD, PhD Objectives—The purpose of this study was to estimate reference ranges for the pulsatility index (PI) of the fetal aortic isthmus in uncomplicated singleton and twin pregnancies during the second half of pregnancy. Methods—We conducted a cross-sectional observational study involving 543 healthy fetuses: 361 singleton pregnancies and 182 twin pregnancies between 19 and 36 weeks’ gestation. The aortic isthmus PI was measured in 2 sonographic planes: the longitudinal aortic arch view and the 3-vessel and trachea view. We evaluated the reproducibility of aortic isthmus PI measurements between these planes by calculating intraclass correlation coefficients and limits of agreement. Scans were performed by 2 physicians, and intraobserver agreement was also measured. Regression analysis was used to estimate gestational age reference values for the aortic isthmus PI. Results—The aortic isthmus PI was significantly correlated with gestational age in singletons and twins during the second half of pregnancy (P < .01). We did not find significant differences between reference ranges in singletons and twins or between the sonographic views. Received March 19, 2014, from the Department of Obstetrics and Gynecology, Hospital General Universitario Gregorio Marañón, Universidad Complutense de Madrid, Madrid, Spain (F.G., P.P., R.M., R.P., L.O.-Q., J.D.L.-L.); and Department of Obstetrics and Gynecology (M.J.R., J.G.) and Research Support Unit (J.M.T.), Hospital la Mancha Centro, Alcázar de San Juan, Ciudad Real, Spain. Revision requested May 6, 2014. Revised manuscript accepted for publication July 16, 2014. This work was supported by the Fondo de Investigaciones Sanitarias (grants FIS PI13/02769 and BA 09/90011). Address correspondence to Juan De León-Luis, MD, PhD, Fetal Medicine Unit, Department of Obstetrics and Gynecology, Hospital General Universitario Gregorio Marañón, Calle O’Donnell 48, 28009 Madrid, Spain. E-mail:
[email protected] Abbreviations
CI, confidence interval; GA, gestational age; ICC, intraclass correlation coefficient; PI, pulsatility index doi:10.7863/ultra.34.4.577
Conclusions—This study offers reference ranges for the aortic isthmus PI during the second half of gestation in singleton and twin pregnancies. Mean aortic isthmus PI values were similar in both types of gestations as well as both sonographic views. The aortic isthmus PI may be reliably obtained from either sonographic view. Key Words—Doppler sonography; fetal aortic isthmus; nomograms; obstetric ultrasound; twin pregnancies
T
he aortic isthmus is a small vascular segment of the aortic arch located between the origin of the left subclavian artery and the aortic joint of the ductus arteriosus (Figure 1). Its anatomic location lends the aortic isthmus a strategic hemodynamic role as an arterial watershed between the brachiocephalic (which includes the brain) and subdiaphragmatic (which includes the placenta) fetal circulations,1,2 directing the flow of blood between these circulatory systems in a preferential fashion in situations of hemodynamic redistribution, such as that which occurs in fetuses with intrauterine growth restriction.3 Sonography of the aortic isthmus was first proposed in 1994 by Fouron et al,4 who examined the longitudinal plane of the aortic arch (Figure 1) by means of complex fluxometric indices. However, because this method was unusual to most obstetricians, various
©2015 by the American Institute of Ultrasound in Medicine | J Ultrasound Med 2015; 34:577–584 | 0278-4297 | www.aium.org
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authors established reference ranges for the aortic isthmus pulsatility index (PI) in the longitudinal view (Figure 1) and in the axial V plane described by Yagel et al5 (3-vessel and trachea view; Figure 2), obtained in normally grown and growth-restricted fetuses but only in singleton pregnancies.6,7 The aim of this study was to estimate reference ranges for the PI of the fetal aortic isthmus in uncomplicated singleton and twin pregnancies during the second half of gestation, emphasizing the data on twin pregnancies.
Materials and Methods We conducted a cross-sectional observational study involving a total of 497 pregnant women between September 2008 and December 2010. Inclusion criteria were as follows: (1) healthy mother and normal pregnancy; (2) consecutive pregnancies referred for routine sonographic examinations; (3) gestational age (GA) at sonography between 19 and 36 weeks; (4) GA and chorionicity determined by firsttrimester sonography; (5) 1 measurement per fetus and
pregnancy; (6) ability to evaluate the aortic isthmus PI in at least 1 of the 2 sonographic planes; (7) complete follow-up of the pregnancy and perinatal results; and (8) healthy neonate confirmed by postnatal clinical examination. Exclusion criteria were as follows: (1) fetal congenital anomaly; (2) sonographically estimated fetal weight below the 10th or above the 90th percentile for GA according to institutionally derived nomograms; and (3) Twin pregnancies in which the difference between the sonographically estimated fetal weight of each twin was greater than 25%. The research protocol was approved by the local Ethics Committee, and informed consent was obtained from all patients. In singletons, to obtain an adequate sample size for estimating the 95th percentile (upper limit of the reference interval), using the PI as the primary indicator, with an expected variability (SD) of 0.25 (as observed in prior studies8) and an accuracy not exceeding one-fourth of the expected variability (0.06), we calculated that 134 patients were needed. We did not find similar studies in twin B
Figure 1. A, Schematic representation of the fetal aortic isthmus location. B, Longitudinal view showing the aortic isthmus location. C, Aortic isthmus Doppler waveform evaluated in the longitudinal aortic arch view. DA indicates ductus arteriosus; LSA, left subclavian artery; and RSA, right subclavian artery.
A
C
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pregnancies that allowed us to perform these calculations. A sample size of at least 8 cases per week of GA in singletons and 5 cases per week in twins was chosen. All calculations were performed with the Ene 3.0 program at the Department of Biometry, GlaxoSmithKline (Madrid, Spain). All scans were performed by 1 of 2 physicians with experience in fetal echocardiography, each of them belonging to 1 of the 2 participating hospitals. Ultrasound scans were performed in the longitudinal aortic arch (Figure 1) and 3-vessel and trachea view (Figure 2) using a transabdominal transducer (LOGIQ 9 Voluson Expert; GE Healthcare, Zipf, Austria; and Aplio XG; Toshiba Medical Systems Co, Ltd, Tokyo, Japan) and following the guidelines of the International Society of Ultrasound in Obstetrics and Gynecology.9 For obtaining the nomograms, we used the method described by Royston and Wright.10 Estimates were made
separately for singleton and twin pregnancies. First, we selected the lowest-degree polynomial (explored up to the third degree) that was best adapted to the data using the least squares method. We then explored the residual data for any changes in the assumptions of normality and homoscedasticity. The latter was obtained by using previous estimates for scaled absolute residuals and a regression model of these residuals over weeks of gestation. For inhomogeneous variance residuals, we chose to model the scaled absolute residuals to be incorporated into the intervals of normality. Finally, we estimated the 5th and 95th percentiles for each week of pregnancy. Intraobserver agreement for the aortic isthmus PI was measured in fetuses with 2 measurements during the same session. Intraclass correlation coefficients (ICCs) and 95% confidence intervals (CIs) were calculated between the first and second sonographic measurements. The agreement was interpreted according to the criteria of Landis and Koch11 B
Figure 2. A, Schematic representation of the fetal aortic isthmus location. B, Transverse view showing the aortic isthmus location (asterisk). C, Aortic isthmus Doppler waveform evaluated in the transverse 3-vessel and trachea view. Abbreviations are as in Figure 1.
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C
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as poor (ICC, 0.80). Similarly, the consistency and reproducibility of aortic isthmus measurements in the 3-vessel and trachea and longitudinal aortic arch sonographic views was estimated by calculating the ICCs in both single and twin pregnancies. In cases of low concordance, the possible presence of proportional or constant systematic errors between both planes was explored. Systematic errors were detected with the aid of graphic (Bland-Altman plots) and analytic (PassingBablok nonparametric regression) methods. A constant systematic error was defined as a situation in which the intercept was not equal to 0, whereas a proportional systematic error was defined as a situation in which the slope differed significantly from the unit. All analyses were performed with PASW 18.0 (IBM Corporation, Armonk, NY) and MedCalc 12.7 (MedCalc, Mariakerke, Belgium) software.
Results The final cohort included 543 fetuses between 19 and 36 weeks’ gestation: 361 healthy singletons (66.5%) and 182 healthy twins (33.5%). Of these, 140 (77%) were dichorionic twins, and 42 (23%) were monochorionic twins. Fifty-two fetuses were excluded (38 singletons and 14 twins) according to the selection criteria cited, including 13 who were lost to follow-up (2.2%). Table 1 shows ICCs and 95% CIs between the first and the second sonographic measurements. Mostly, the intraobserver agreement was fair or moderate according to the criteria of Landis and Koch.11 The interchangeability between the sonographic views was analyzed with the aid of Passing-Bablok nonparametric regression, which detected constant and proportional systematic errors between both planes for the aortic isthmus PI, especially in singleton fetuses (Table 2). We thus decided to evaluate the reproducibility between planes in these fetuses with a Bland-Altman plot, observing that the average difference in the measured PI between the views was –0.14 (Figure 3).
Regression equations representing the relationships between the variables studied and GA are shown in Table 3. We observed a slight increase in the PI with GA. This increase was linear (a constant increment for each additional week of gestation) except for the longitudinal aortic arch plane in twin pregnancies, which had a quadratic increase. Singletons Nomograms for the aortic isthmus PI between 19 and 36 weeks’ gestation were obtained in both the 3-vessel and trachea view and the longitudinal aortic arch view. In both cases, the adjustment could be made with a simple firstdegree polynomial without the need for a renewal process for residuals. We were able to measure 249 fetuses (69%) in both sonographic views. In those fetuses, a comparison between PI values obtained from both views was performed. We found no statistically significant differences between the views (P > .05). The nomograms obtained are shown in Figures 4 and 5. The predicted mean values for each week of gestation along with their 5th and 95th percentiles are shown in Tables 4 and 5. Twins Nomograms for the aortic isthmus PI between 19 and 36 weeks’ gestation were obtained in both the 3-vessel and trachea view and the longitudinal aortic arch view. In the 3-vessel and trachea view, a linear adjustment without residual scaling was enough, but data from the longitudinal aortic arch view had to be adjusted with a second-degree polynomial with no additional adjustments for residuals. We were able to measure 89 fetuses (61%) in both sonographic views. In those fetuses, a comparison between PI values obtained from both views was performed. We found no statistically significant differences between the views (P > .05). The nomograms obtained are shown in Figures 6 and 7. The predicted mean values for each week of gestation along with their 5th and 95th percentiles are shown in Tables 6 and 7.
Table 1. Intraobserver Agreement for the Aortic Isthmus PI ICC (95% CI) Pregnancies All Singletons Twins
3VT
LAA
0.53 (0.36 to 0.66) (n = 96) 0.55 (0.37 to 0.68) (n = 79) 0.41 (–0.08 to 0.74) (n = 17)
0.15 (–0.12 to 0.40) (n = 52) 0.15 (–0.15 to 0.42) (n = 45) 0.23 (–0.52 to 0.80) (n = 7)
LAA indicates longitudinal aortic arch view; and 3VT, 3-vessel and trachea view.
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Discussion First, our results show that fetal aortic isthmus Doppler measurements are reproducible. This study shows reference ranges for the aortic isthmus PI between 19 and 36 weeks’ gestation in singleton and twin pregnancies. We did not find significant differences between the references ranges for the sonographic views analyzed. Finally, the aortic isthmus PI had a positive linear correlation with GA (P < .01). Because the fetal aortic isthmus is not routinely examined in clinical practice, our first step was to analyze several methodological strategies to facilitate its implementation. Table 2. Reproducibility of Aortic Isthmus PI Measurements Between Sonographic Planes Pregnancies All Singletons Twins
Constant (95% CI)
Slope (95% CI)
–0.41 (–0.73 to –0.10) –0.38 (–0.71 to –0.08) –0.74 (–1.82 to 0.31)
1.12 (1.00 to 1.25) 1.11 (0.99 to 1.24) 1.29 (0.85 to 1.68)
Passing-Bablok nonparametric regression.
Figure 3. Bland-Altman plot for the aortic isthmus PI in singleton pregnancies.
We thus assessed the agreement of aortic isthmus measurements and their reproducibility between the sonographic views in which this vascular segment can be visualized. We considered analyzing the PI against other parameters proposed by various authors12 because it is the parameter most often used for studying other vascular territories. Moreover, it is useful for making comparisons with other vascular territories as well as being easy to obtain from automatic sonographic calculations. In the intraobserver agreement analysis, according to the classification system of Landis and Koch,11 aortic isthmus PI values had either fair or moderate agreement in both types of gestations (Table 1). At this point, one of the study limitations became apparent: namely, that interobserver agreement could not be evaluated by having the physicians perform their measurements consecutively on the same patient during the same visit. Considering that the study was conducted in 2 hospitals in different cities, this difficulty was obviously insurmountable. One relevant aspect was the estimation of agreement between the 3-vessel and trachea and longitudinal aortic arch sonographic views. If these could be used interchangeably, obtaining the Doppler and aortic isthmus parameters would be much easier, thus shortening examination times. Figure 4. Aortic isthmus PI nomogram for singletons: 3-vessel and trachea view.
Table 3. Regression Equations for Aortic Isthmus PI as a Function of GA Parameter Singletons Constant (intercept) GA Twins Constant (intercept) GA GA2
3VT
LAA
2.169 0.016
2.072 0.014
2.006 0.017
5.112 –0.242 0.005
Figure 5. Aortic isthmus PI nomogram for singletons: longitudinal aortic arch view.
Abbreviations are as in Table 1.
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In this context, the proposal by Del Río et al6 to use the most accessible plane was an important step. According to our data, the agreement for the aortic isthmus PI was fair in singleton pregnancies and good in twins. The results obtained with the Passing-Bablok test for nonparametric regression (Table 2) and with the Bland-Altman plot (Figure 3) provide sufficiently reliable assurance of the interchangeability of the results obtained from either sonographic plane. Table 4. Aortic Isthmus PI Reference Values for Singletons: 3-Vessel and Trachea View (n = 339) GA, wk
n
Mean
5th
95th
19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36
10 23 11 8 8 8 21 21 15 25 28 29 15 19 28 41 17 12
2.47 2.487 2.503 2.519 2.535 2.551 2.567 2.583 2.599 2.615 2.631 2.647 2.663 2.678 2.694 2.710 2.726 2.742
1.65 1.675 1.691 1.708 1.724 1.740 1.756 1.773 1.789 1.805 1.821 1.836 1.852 1.868 1.884 1.899 1.915 1.930
3.285 3.300 3.315 3.331 3.346 3.362 3.377 3.393 3.409 3.425 3.441 3.457 3.473 3.489 3.505 3.521 3.538 3.554
In our study, the number of successful recordings was high for the 3-vessel and trachea view compared to the longitudinal aortic arch view in singletons and twins. These differences could be explained by the fact that the 3-vessel and trachea view is an easier plane for the sonographer because it is part of routine fetal heart examinations. Once these methodological aspects had been examined, we estimated the reference ranges for the fetal aortic isthmus PI in low-risk singleton and twin pregnancies. Such specific fetal nomograms are useful for discriminating normal from abnormal measurements at a particular point in development, as well as for defining patterns of change over time until the 36th week of gestation. One of the strengths of this study was that it set out to determine whether Doppler measurements of the fetal aortic isthmus could be obtained in twins, with a secondary goal of determining whether these measurements were similar to those obtained in singleton pregnancies. The answers to these questions are important because they could pave the way for future investigations concerning the clinical usefulness of prenatal hemodynamic measurements in pathologic singleton and twin pregnancies. The failure rates in obtaining aortic isthmus measurements were 19.7% in twin pregnancies and 6.1% in singleton pregnancies, with failure more likely to occur toward the end of pregnancy. Figure 6. Aortic isthmus PI nomogram for twins: 3-vessel and trachea view.
Table 5. Aortic Isthmus PI Reference Values for Singletons: Longitudinal Aortic Arch View (n = 263) GA, wk
n
Mean
5th
95th
19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36
12 18 10 8 8 8 16 19 18 18 20 19 12 13 17 24 12 11
2.337 2.351 2.365 2.379 2.393 2.407 2.421 2.435 2.449 2.463 2.477 2.491 2.504 2.518 2.532 2.546 2.560 2.574
1.485 1.500 1.515 1.530 1.544 1.559 1.573 1.587 1.601 1.615 1.629 1.643 1.657 1.670 1.684 1.697 1.710 1.723
3.188 3.202 3.215 3.228 3.241 3.255 3.269 3.282 3.296 3.310 3.324 3.338 3.352 3.367 3.381 3.396 3.410 3.425
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Figure 7. Aortic isthmus PI nomogram for twins: longitudinal aortic arch view.
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These findings could be explained in part by the fact that the spine is more calcified in later gestation, and the visualization of the aortic arch is more difficult. For calculating reference values, we designed a crosssectional opportunity sampling model in which each fetus included in the study contributed a single measurement. This model was chosen over longitudinal sampling (which measures the same fetus several times at different points in Table 6. Aortic Isthmus PI Reference Values for Twins: 3-Vessel and Trachea View (n = 146) GA, wk
n
Mean
5th
95th
19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36
5 5 5 5 5 15 5 11 11 8 13 12 10 8 9 9 5 5
2.335 2.353 2.370 2.387 2.405 2.422 2.439 2.457 2.474 2.491 2.509 2.526 2.543 2.561 2.578 2.595 2.613 2.630
1.594 1.614 1.633 1.652 1.671 1.690 1.708 1.726 1.744 1.761 1.778 1.795 1.811 1.827 1.843 1.859 1.874 1.889
3.076 3.091 3.107 3.122 3.138 3.154 3.170 3.187 3.204 3.222 3.239 3.257 3.275 3.294 3.313 3.332 3.351 3.371
Table 7. Aortic Isthmus PI Reference Values for Twins: Longitudinal Aortic Arch View (n = 94) GA, wk
n
Mean
5th
95th
19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36
5 5 5 5 5 6 5 8 5 5 5 5 5 5 5 5 5 5
2.310 2.262 2.224 2.196 2.178 2.170 2.171 2.183 2.205 2.236 2.278 2.329 2.390 2.462 2.543 2.634 2.735 2.846
1.563 1.530 1.500 1.477 1.460 1.451 1.452 1.463 1.485 1.517 1.559 1.611 1.673 1.742 1.818 1.899 1.983 2.069
3.058 2.995 2.948 2.916 2.896 2.888 2.890 2.903 2.924 2.956 2.996 3.047 3.108 3.181 3.268 3.369 3.487 3.623
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the pregnancy) not only because it is the most widely used design for such studies but also because it is less sensitive to case loss, since it requires no follow-up. Moreover, it better represents the study population, as it includes a higher number of fetuses. The disadvantages of this strategy include greater variability among observations and the greater difficultly and time required to recruit an adequately sized sample. In uncomplicated pregnancies, the aortic isthmus diastolic waveform is consistently anterograde and might show a retrograde pattern in cases of brain flow redistribution in fetuses affected by intrauterine growth restriction.1 Our aortic isthmus PI nomograms showed a slight increase in the index values throughout pregnancy in both types of pregnancies and also in both sonographic views (Figures 4–7 and Tables 4–7). These variations suggest that the aortic isthmus PI is a useful parameter for detecting abnormalities in the fetal aortic isthmus, since knowledge of the normal variations that occur during gestation may facilitate hemodynamic assessment of the fetus. Our data are in accordance with the findings of other authors8 and may be explained by the decrease in the middle cerebral artery PI in the third trimester. The results obtained in twins suggest that the aortic isthmus PI values in uncomplicated singleton and twin pregnancies are similar and are not affected by twin order or chorionicity. To the best of our knowledge, this finding is novel, since we were unable to find similar studies in the literature with adequate sample sizes for the variables under study. Experimental studies in animal models have attempted to establish the role of the aortic isthmus in fetal circulation.13–15 These studies, despite their limitations, showed a strong positive correlation between placental flow and flow in the aortic isthmus of ovine fetuses subjected to a gradual increase in placental resistance through compression of the umbilical vein. The conclusion was that in animal models, states of chronic hypo-oxygenation were associated with an increase in vascular resistance, with various degrees of retrograde flow in the aortic isthmus. Clinical studies in human fetuses have likewise shown the usefulness of aortic isthmus assessment in cases of placental insufficiency.16,17 Several data show that the aortic isthmus is not only a marker of fetal well-being, but it also acts as a predictor of perinatal results. Especially remarkable is the relationship between the aortic isthmus retrograde diastolic flow and the presence of an adverse perinatal outcome.18–21 Our nomograms may thus be useful for monitoring growth-restricted fetuses, considering aortic isthmus PI values above the 95th percentile as being altered.
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In summary, our results allow us to make the following observations: (1) The intraobserver agreement for the aortic isthmus PI is moderate, according to the criteria of Landis and Koch.11 (2) Aortic isthmus measurements can be taken either in the 3-vessel and trachea or longitudinal aortic arch sonographic view because their values are interchangeable. (3) In both singleton and twin pregnancies, the aortic isthmus PI shows a slight but significant tendency to increase with GA during the second half of pregnancy. (4) Mean 5th and 95th percentiles for the aortic isthmus PI show similar values in both singleton and twin pregnancies. (5) Our normality curves may be clinically useful for management of fetuses with restricted growth.
References 1.
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