A. SZWAST*, Z. TIAN*, M. McCANN*, D. DONAGHUE*, M. BEBBINGTON, M. JOHNSON, R. D. WILSON and J. RYCHIK*

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1 Ultrasound Obstet Gynecol 2007; 30: Published online 29 May 2007 in Wiley InterScience ( DOI: /uog.4032 Impact of altered loading conditions on ventricular performance in fetuses with congenital cystic adenomatoid malformation and twin twin transfusion syndrome A. SZWAST*, Z. TIAN*, M. McCANN*, D. DONAGHUE*, M. BEBBINGTON, M. JOHNSON, R. D. WILSON and J. RYCHIK* *Department of Pediatrics, Cardiology Division, Fetal Heart Program and Department of Surgery, Center for Fetal Diagnosis and Treatment, Children s Hospital of Philadelphia, Philadelphia, PA, USA KEYWORDS: cardiac performance; CCAM; fetal Doppler; fetal heart; TTTS ABSTRACT Objectives In the fetus with a structurally normal heart, two conditions giant chest mass, such as congenital cystic adenomatoid malformation (CCAM), and twin twin transfusion syndrome (TTTS) alter ventricular loading conditions and may result in cardiovascular compromise. The aim of this study was to elucidate the mechanism of cardiovascular dysfunction by comparing geometryindependent, Doppler flow-derived measures of ventricular performance in fetuses with altered loading conditions vs. those in normal fetuses. Methods Doppler flow-derived measures of myocardial performance index (MPI) as described by Tei, ventricular ejection force as described by Isaaz, and combined cardiac output (CCO) were obtained by echocardiography in fetuses with a normal cardiovascular system (n = 76) or CCAM (n = 36) and fetal partners with TTTS (n = 22). Results In the CCAM group, systolic performance as evidenced by the ejection forces was preserved, right ventricular (RV) MPI was increased and CCO diminished, suggesting diastolic dysfunction and poor filling secondary to cardiac compression and a tamponade effect. In TTTS, recipient twins exhibited greater left ventricular (LV) ejection forces and higher CCO than donor twins, and had abnormal RV and LV MPI, reflecting increased preload, preserved left systolic performance, but diastolic dysfunction. Donor twins had diminished ejection forces and CCO in comparison with normal controls and recipient partners, reflecting hypovolemia. Conclusions In both CCAM and recipient twins of the TTTS, diastolic dysfunction plays a significant role in the pathophysiology of each disorder and precedes changes in systolic performance. Measures of ventricular performance can help elucidate poorly understood mechanisms of cardiovascular compromise in the developing fetus. Copyright 2007 ISUOG. Published by John Wiley & Sons, Ltd. INTRODUCTION A variety of disorders can impact secondarily on the developing cardiovascular system by altering ventricular preload or afterload, resulting in a compromised fetus with a structurally normal heart. The precise pathophysiological mechanism of cardiovascular dysfunction in these disorders is often poorly understood. For example, large intrathoracic masses such as a congenital cystic adenomatoid malformation (CCAM) have been found to compress the heart 1. Some fetuses with a large CCAM develop hydrops 1 3 ; however, the relationship between possible alterations in ventricular performance and the development of hydrops has not been fully delineated. In twin twin transfusion syndrome (TTTS), placental vasculopathy results in an imbalance of blood flow within the two fetal circulations and a discordance in fetal size 4 6. Oligohydramnios is seen in the donor twin whereas polyhydramnios, ventricular hypertrophy, ventricular dysfunction and progressive cardiomyopathy can develop in the recipient twin 7 9. We hypothesize that abnormalities of ventricular performance in the recipient twin may herald the development of overt cardiomyopathy and that these abnormalities may exist early in the development of the disease. In both CCAM and TTTS, diastolic dysfunction may play a significant role in the pathophysiology of each disorder. In order to distinguish between systolic and diastolic dysfunction, we applied three Doppler-derived, geometry-independent Correspondence to: Dr A. Szwast, Department of Pediatrics, Children s Hospital of Philadelphia, 2 nd Floor Main, Division of Cardiology, 34 th Street and Civic Center Boulevard, Philadelphia, PA 19050, USA ( szwast@ .chop.edu) Accepted: 26 January 2007 Copyright 2007 ISUOG. Published by John Wiley & Sons, Ltd. ORIGINAL PAPER

2 Ventricular performance in fetuses with altered loading conditions 41 measures of ventricular performance: myocardial performance index (MPI) 10,11, ventricular ejection force 12 and cardiac output 13,14. All of these measurements have been described previously and validated in the fetus The purpose of our study was to use these indices of ventricular performance to help clarify the pathophysiology of CCAM and TTTS. METHODS Study population Institutional review board approval for this crosssectional retrospective study and review of the data was obtained. The study population consisted of pregnant women referred for fetal echocardiography to the Fetal Heart Program at the Cardiac Center of the Children s Hospital of Philadelphia from November 2004 to May Fetuses considered for inclusion in this analysis were (1) those with normal cardiovascular anatomy and no extracardiac anatomical abnormalities of hemodynamic significance and whose mothers had normal uteroplacental function (normal controls), (2) fetuses with a large chest mass with CCAM, and (3) monochorionic twins diagnosed with TTTS. Exclusion criteria included a gestational age of less than 16 weeks or greater than 40 weeks, persistent non-sinus rhythm, hydrops fetalis, incomplete datasets, or any maternal condition that might affect fetal hemodynamics, such as gestational diabetes, thyroid disease or pre-eclampsia. All fetuses with CCAM underwent magnetic resonance imaging to confirm the anatomy and to document the type and position of the mass. In all studies, the CCAM was described as large by the interpreting radiologist. TTTS was diagnosed in monochorionic twins if there was a discrepancy in size of > 20%, oligohydramnios in the smaller donor, and polyhydramnios in the larger recipient twin. In some donor twins, there was evidence of an abnormal umbilical arterial flow pattern with diminished diastolic flow, whereas in some recipient twins there was evidence of ventricular hypertrophy and/or tricuspid regurgitation. Quintero staging 22 was performed in all fetuses at the time of initial evaluation. Fetal echocardiography A complete fetal echocardiogram was performed using a Siemens Acuson Sequoia 256 system (Mountain View, CA, USA) coupled with a 6C2 transducer. Although some fetuses were imaged more than once, only the first evaluation at our institution was analyzed in order to evaluate ventricular performance at the time of initial presentation. Gestational age varied from 17 to 40 weeks. Pregnancy duration was estimated from the last menstrual period and confirmed by ultrasound measurement. Multiple two-dimensional (2D) views of the heart were obtained to evaluate fetal cardiac anatomy, as described previously 23. All images were recorded digitally as clips or stillframe images and stored in our fetal database (Siemens KinetDx). Pulsed Doppler signals were obtained at the tips of the tricuspid and mitral valves from an apical four-chamber view in diastole, and at the annuli of the pulmonic or aortic valves in the outflow tract views in systole. All Doppler recordings were obtained at an insonation angle of < 10 to flow. Angle correction was not used. Measurements of the pulmonic and aortic annuli diameters were made in systole at right angles to the plane of flow. Doppler measurements Measurements were performed using KinetDx cardiovascular imaging software. The MPI of Tei is a global measure of combined systolic and diastolic performance 10,11.Itis defined as the sum of the isovolumic contraction time and the isovolumic relaxation time divided by the ejection time. The combined isovolumic times may be obtained by subtracting the aortic or pulmonic ejection time from the period between the cessation of flow and the onset of flow of either the mitral or tricuspid inflow signal. A higher MPI value corresponds to a greater degree of total ventricular dysfunction, but does not distinguish between systolic and diastolic dysfunction. The ventricular ejection force is calculated according to Isaaz s formula 12. The formula describes the acceleration of blood across the pulmonic or aortic valve over a specific time interval, and is a reflection of systolic ventricular performance derived from Newton s laws. A higher value corresponds to greater force exerted in ejecting the ventricular volume of blood during systole. Ventricular ejection force = (1.055 cross-sectional area of valve velocity time integral during acceleration phase) (peak systolic velocity of Doppler envelope/time to peak velocity), where represents the density of blood. Finally, the combined cardiac output (CCO) is determined by adding the right and left cardiac outputs, individually calculated according to the formula: semilunar valve cross-sectional area fetal heart rate velocity time integral across the valve in systole 13,14. CCO values were indexed to the estimated weight in kilograms. For all Doppler-derived measurements, at least three uniform signals were measured and the results averaged for further analysis. 2D measurements For all 2D measurements, the valve annulus was measured in systole on a frozen image at the hinge points of the valve by the leading edge to trailing edge method. At least three separate measurements were made and the results averaged. The aortic valve annulus was determined from the long axis of the left heart. The pulmonary valve annulus was obtained from the right ventricle outflow tract view 23. Statistical analysis Right ventricular (RV) and left ventricular (LV) MPI as well as CCO indexed to fetal weight did not vary

3 42 Szwast et al. significantly over the course of gestation in the normal control population. Consequently, unpaired two-tailed Student s t-tests were used to compare these values in the normal population with those in CCAM, donor twin and recipient twin populations. Ejection force, on the other hand, did vary significantly with gestational age. Polynomial regression analysis was used to demonstrate the relationship between gestational age and ejection force for all groups. To test the hypothesis that the ejection forces of the CCAM, donor twin and recipient twin populations differed from those of the normal population, a univariate generalized linear model was constructed with gestational age as the predictor variable, RV or LV ejection force (RVEF and LVEF, respectively) as the dependent variable and study group as the fixed factor. Because the SD of the ejection force increases significantly with gestational age, a log 10 transformation of the RVEF and LVEF was performed in order to stabilize variance. Review of the log 10 -transformed data revealed normal distributions. F-tests were performed to assess the between-group effect. If significant, pairwise comparisons between the estimated marginal means as determined by the linear model were subsequently performed and the mean difference determined for the purposes of statistical analysis. Paired Student s t-tests were used to compare estimated fetal weight, MPI, indexed CCO and ejection force between the donor twin and the recipient twin. All values were considered significantly different at P < RESULTS Study population The study population comprised 76 normal fetuses (mean ± SD gestational age 25.9 ± 5.3 weeks), 36 fetuses with CCAM (mean ± SD gestational age 25.3 ± 4.4 weeks), and 22 pairs of fetuses with TTTS (mean ± SD gestational age 21.3 ± 2.4 weeks). Of the 36 fetuses with a CCAM, 56% of lesions were located in the right lung and 44% in the left. Half of the subjects had evidence of mediastinal shift; 33% were macrocystic masses and 66% were homogeneous or microcystic masses. None of the 36 fetuses with CCAM had evidence of hydrops, as hydrops fetalis itself may result in Doppler echocardiographic changes that may mask the original physiology. Of the 22 fetuses with TTTS, 32% were Quintero Stage 1, 27% Quintero Stage 2 and 41% Quintero Stage 3. None of the twin twin pairs was Quintero Stage 4 or 5 at the time of initial evaluation. Findings in normal control population Results for the normal group are summarized in Table 1. There was no significant correlation between gestational age and RV MPI (r = 0.04, P = 0.75), LV MPI (r = 0.18, P = 0.12) or indexed CCO (r = 0.09, P = 0.42) for our normal control group. However, RVEF and LVEF correlated strongly with gestational age (RVEF: r = 0.90, P < 0.001; LVEF: r = 0.91, P < 0.001). Figure 1 demonstrates the polynomial regression of gestational age vs. RVEF and LVEF for the normal control population. Table 2 demonstrates the generalized linear model predicting log 10 LVEF and log 10 RVEF based on gestational age with the coefficient of beta adjusted for the effect of the group. Findings in CCAM population Results for the CCAM group compared with normal controls are summarized in Table 1. The RV MPI was significantly higher in the CCAM group than in the normal group; however, the LV MPI was not statistically different Ventricular ejection force (mn) Gestational age (weeks) Figure 1 Polynomial regression slopes for gestational age (GA) vs. right ventricular ejection force (solid line, RVEF = GA GA 2.9; r 2 = 0.82, P < 0.001) and left ventricular ejection force (dashed line, LVEF = GA GA 8.0; r 2 = 0.83, P < 0.001) for the normal control population. Individual values of RVEF (ž) and LVEF ( ) for the normal control population are shown. Table 1 Gestational age, myocardial performance index (MPI) and combined cardiac output (CCO) Variable Normal control (n = 76) CCAM (n = 36) Donor twin (n = 22) Recipient twin (n = 22) Gestational age (weeks) 25.9 ± ± ± 2.4** 21.3 ± 2.4** RV MPI 0.43 ± ± 0.07** 0.36 ± 0.06** 0.58 ± 0.10** LV MPI 0.40 ± ± ± 0.07** 0.54 ± 0.12** CCO (ml/min/kg) 477 ± ± 87** 407 ± 69** 537 ± 111* Values are mean ± SD. *P < 0.05, **P < vs. normal control; P < vs. donor twin. CCAM, congenital cystic adenomatoid malformation; LV, left ventricular; RV, right ventricular.

4 Ventricular performance in fetuses with altered loading conditions 43 Table 2 Generalized linear models predicting log 10 -transformed left (LVEF) and right (RVEF) ventricular ejection forces based on gestational age (GA) with the coefficient of beta adjusted for effect of the group LVEF RVEF Parameter Parameter estimate Standard error Estimated marginal mean at 24.4 weeks P Parameter estimate Standard error Estimated marginal mean at 24.4 weeks P Intercept GA Normal control CCAM Recipient twin < Donor twin < < In the models, all parameter estimates were statistically significant (P < 0.001). The between-group effects were statistically significant (LVEF: F = 27.3, P < 0.001; RVEF:F = 16.6, P < 0.001). Consequently, based on the linear models, the estimated marginal means were calculated at 24.4 weeks gestation and pairwise comparisons of the estimated marginal means to the normal group were made (LVEF: r 2 = 0.81, P < 0.001; RVEF:r 2 = 0.82, P < 0.001). CCAM, congenital cystic adenomatoid malformation. Left ventricular ejection force (mn) Gestational age (weeks) Right ventricular ejection force (mn) Gestational age (weeks) Figure 2 Congenital cystic adenomatoid malformation (ž), recipient twin ( ) and donor twin ( ) left ventricular ejection force vs. gestational age plotted on the normal control population polynomial regression curve with 95% CI. from that in controls. The CCO was significantly lower in the CCAM group than in the normal control group, although the RVEF and LVEF were not significantly different from normal control values (Table 2). Figures 2 and 3 demonstrate the LVEF and RVEF for the CCAM population plotted on a regression curve with 95% CI for the normal control population. Findings in twin twin transfusion pairs Comparison of results for the donor twins, recipient twins and normal control fetuses are summarized in Table 1. Figures 2 and 3 demonstrate the LVEF and RVEF for the donor twin and recipient twin populations plotted on a regression curve with 95% CI for the normal control population. The median estimated fetal weight of the donor twin was 0.29 (range, ) kg whereas that of the recipient twin was 0.42 (range, ) kg (P < 0.001). As expected, donor twins were significantly smaller in size than recipient twins. Figure 3 Congenital cystic adenomatoid malformation (ž), recipient twin ( ) and donor twin ( ) right ventricular ejection force vs. gestational age plotted on the normal control population polynomial regression curve with 95% CI. Donor twins had lower RV and LV MPI, RVEF and LVEF, and indexed CCO compared with recipient twins as well as compared with normal controls. In contrast, recipient twins had abnormally increased RV and LV MPI and LVEF compared with normal fetuses. The RVEF in recipient twins was not significantly different from that of the normal control population. Finally, recipient twins had a higher CCO than normal controls. DISCUSSION Doppler-derived, geometry-independent measures of ventricular performance have been described previously and validated in the fetus Several studies have shown that the MPI is independent of heart rate and ventricular geometry, and is simple to measure without the need for precise anatomical imaging. Studies by Tsutsumi et al. demonstrate higher MPI values in midto late-gestational age fetuses with intrauterine growth

5 44 Szwast et al. restriction and maternal diabetes mellitus than in normal controls 20. Similarly, in fetuses with congestive heart failure, the MPI is increased 24,25. The ventricular ejection force, as described by Isaaz, is based on Newton s second law of motion and estimates the energy transferred from ventricular myocardial shortening to work done by accelerating blood into the circulation 12. Doppler studies performed in adults have demonstrated a close correlation between the LVEF and LV ejection fraction, a reliable measure of systolic performance 12. Rizzo et al. demonstrated that fetuses with intrauterine growth restriction secondary to uteroplacental insufficiency have a significant decrease in the ejection forces of both ventricles 26. Finally, Doppler-derived calculation of the cardiac output provides a standardized assessment of ventricular function by measuring the amount of blood ejected by the heart. Reference ranges for the MPI, ventricular ejection force and CCO for the normal fetus have been published previously Similar to previous findings, we found no significant change in the RV or LV MPI 17,18,25 or CCO indexed to fetal weight 21 over the course of gestation. Our study reveals a number of interesting findings that help explain the cardiovascular pathophysiology of the disorders evaluated. None of our population of fetuses with CCAM had hydrops fetalis. RVEF and LVEF did not vary significantly from values in the normal control population, suggesting that systolic function is normal in fetuses with CCAM without evidence of hydrops. However, RV diastolic function is impaired in that RV MPI is abnormally raised and indexed CCO is diminished. Our study demonstrates a 15% decrease in CCO compared with that in normal controls. We hypothesize that the giant lung mass compresses the heart in fetuses with CCAM and impedes ventricular diastolic excursion, thereby limiting ventricular filling. The mass may also exert a mild pressure load on both ventricles of the fetal heart. The right ventricle performs the majority of work in utero, generating 60% of the CCO 27,28. Therefore, the right ventricle may be more susceptible to changes in loading conditions. Reller et al. demonstrated that the right ventricle is more than five times more sensitive to increases in arterial pressure than is the left ventricle 29. Consequently, in response to an arterial load, the RV stroke volume decreased to a greater extent than the LV stroke volume 29,30. We hypothesize that the pressure-loaded right ventricle hypertrophies in order to become a more efficient pump; however, the stroke volume is not normalized. As a result, the CCO generated by the fetus with a giant lung mass is diminished, despite normal systolic function. These findings underscore that diastolic dysfunction is primarily responsible for the decreased cardiac output in fetuses with CCAM before the onset of hydrops fetalis. In the fetal pairs affected by TTTS, chronic shunting of blood through placental vascular anastomoses away from the donor and towards the recipient leads to hypovolemia and oligohydramnios in the donor, and hypervolemia and polyhydramnios in the recipient 4 6,22, The donor fetus experiences a marked increase in vascular resistance and hence increased afterload 34. Our findings of lower ejection forces and lower CCO in the donor twins are consistent with the observed hypovolemia and increased afterload. MPI is lower in the donor twins than in normal controls, suggesting normal or even improved ventricular compliance. Hence, abnormalities of ventricular function are rarely seen in the donor twin population of TTTS. In contrast, we found that recipient twins have increased MPI and CCO compared with the normal control population. It is known that recipient twins may exhibit progressive ventricular hypertrophy and, as a consequence, diminished diastolic compliance 7,8. Various studies have suggested that hormonal mediators, such as vasopressin and angiotensin II, are released by donor twins to compensate for chronic hypovolemia 5, These mediators, in addition to the volume load, may cross the placenta from donor to recipient and act on the recipient twin to alter the myocardial make-up, with eventual development of ventricular hypertrophy 7 9. Indexed CCO is increased compared with that in normal controls and is likely to be secondary to the increased preload. There was great heterogeneity in systolic performance, as was evident from the wide variance in ejection forces in our recipient twin population. As previously seen in cases of severe TTTS, RV systolic performance was more severely affected than LV systolic performance in our recipient twin population 7,8. Consequently, the LVEF was increased compared with normal control values, although the RVEF was not significantly different. Some fetuses had a higher RVEF than normal control values, but others had evidence of a RV cardiomyopathy characterized by severe tricuspid regurgitation and decreased forward flow through the pulmonary annulus. Utilization of these Doppler-derived parameters helps to identify fetuses with diastolic dysfunction before the onset of low cardiac output and hydrops, and may therefore be helpful in grading the magnitude of disease as the twin twin transfusion progresses. In summary, our study shows that diastolic dysfunction may be responsible for impaired ventricular filling leading to a decreased indexed CCO despite normal systolic function in fetuses with CCAM without evidence of hydrops fetalis. In the TTTS, the donor twin exhibits improved myocardial performance indices yet decreased ejection forces and decreased CCO compared with normal controls. In contrast, the recipient twin exhibits diastolic dysfunction with increased MPIs and increased cardiac outputs. In our population of recipient twins, the right ventricle was more severely affected than the left, as evidenced by normal or decreased RVEF in spite of increased preloads. Our data help clarify the pathophysiological processes underlying these disorders. Our findings also support the routine incorporation of Doppler-derived parameters of ventricular performance in the fetus with complex cardiovascular physiology in which loading conditions are altered. By determining the MPI,

6 Ventricular performance in fetuses with altered loading conditions 45 a measure of global ventricular function incorporating systolic and diastolic time intervals, in tandem with the ventricular ejection force, a measure of systolic function, the mechanism underlying ventricular compromise may be elucidated. Determination of the indexed cardiac output adds to the assessment of fetal well-being and global ventricular function. Further application of these parameters in other disease processes may prove to be of importance in expanding our understanding of the mechanisms of cardiovascular compromise in the fetus. ACKNOWLEDGMENTS Dr Szwast was supported by a National Institutes of Health training grant (T32-HL ). REFERENCES 1. Mahle WT, Rychik J, Tian ZY, Cohen MS, Howell LJ, Crombleholme TM, Flake AW, Adzick NS. Echocardiographic evaluation of the fetus with congenital cystic adenomatoid malformation. Ultrasound Obstet Gynecol 2000; 16: Taguchi T, Suita S, Yamanouchi T, Nagano M, Satoh S, Koyanagi T, Nakano H. Antenatal diagnosis and surgical management of congenital cystic adenomatoid malformation of the lung. Fetal Diagn Ther 1995; 10: Miller JA, Corteville JE, Langer JC. Congenital cystic adenomatoid malformation in the fetus: natural history and predictors of outcome. JPediatrSurg1996; 31: van Gemert MJ, Umur A, Tijssen JG, Ross MG. Twin twin transfusion syndrome: etiology, severity and rational management. Curr Opin Obstet Gynecol 2001; 13: Galea P, Jain V, Fisk NM. Insights into the pathophysiology of twin twin transfusion syndrome. Prenat Diagn 2005; 25: Wee LY, Fisk NM. The twin twin transfusion syndrome. Semin Neonatol 2002; 7: Zosmer N, Bajoria R, Weiner E, Rigby M, Vaughan J, Fisk NM. Clinical and echographic features of in utero cardiac dysfunction in the recipient twin in twin twin transfusion syndrome. Br Heart J 1994; 72: Barrea C, Alkazaleh F, Ryan G, McCrindle BW, Roberts A, Bigras JL, Barrett J, Seaward GP, Smallhorn JF, Hornberger LK. Prenatal cardiovascular manifestations in the twin-to-twin transfusion syndrome recipients and the impact of therapeutic amnioreduction. Am J Obstet Gynecol 2005; 192: Fesslova V, Villa L, Nava S, Mosca F, Nicolini U. Fetal and neonatal echocardiographic findings in twin twin transfusion syndrome. Am J Obstet Gynecol 1998; 179: Tei C, Nishimura RA, Seward JB, Tajik AJ. Noninvasive Doppler-derived myocardial performance index: correlation with simultaneous measurements of cardiac catheterization measurements. J Am Soc Echocardiogr 1997; 10: Tei C, Ling LH, Hodge DO, Bailey KR, Oh JK, Rodeheffer RJ, Tajik AJ, Seward JB. New index of combined systolic and diastolic myocardial performance: a simple and reproducible measure of cardiac function a study in normals and dilated cardiomyopathy. J Cardiol 1995; 26: Isaaz K, Ethevenot G, Admant P, Brembilla B, Pernot C. A new Doppler method of assessing left ventricular ejection force in chronic congestive heart failure. Am J Cardiol 1989; 64: Huntsman LL, Stewart DK, Barnes SR, Franklin SB, Colocousis JS, Hessel EA. Noninvasive Doppler determination of cardiac output in man. Clinical validation. Circulation 1983; 67: Dubin J, Wallerson DC, Cody RJ, Devereux RB. Comparative accuracy of Doppler echocardiographic methods for clinical stroke volume determination. Am Heart J 1990; 120: Mielke G, Benda N. Cardiac output and central distribution of blood flow in the human fetus. Circulation 2001; 103: Sutton MS, Gill T, Plappert T, Saltzman DH, Doubilet P. Assessment of right and left ventricular function in terms of force development with gestational age in the normal human fetus. Br Heart J 1991; 66: Eidem BW, Edwards JM, Cetta F. Quantitative assessment of fetal ventricular function: establishing normal values of the myocardial performance index in the fetus. Echocardiography 2001; 18: Friedman D, Buyon J, Kim M, Glickstein JS. Fetal cardiac function assessed by Doppler myocardial performance index (Tei Index). Ultrasound Obstet Gynecol 2003; 21: Raboisson MJ, Bourdages M, Fouron JC. Measuring left ventricular myocardial performance index in fetuses. Am J Cardiol 2003; 91: Tsutsumi T, Ishii M, Eto G, Hota M, Kato H. Serial evaluation for myocardial performance in fetuses and neonates using a new Doppler index. Pediatr Int 1999; 41: De Smedt MC, Visser GH, Meijboom EJ. Fetal cardiac output estimated by Doppler echocardiography during mid- and late gestation. Am J Cardiol 1987; 60: Quintero RA, Morales WJ, Allen MH, Bornick PW, Johnson PK, Kruger M. Staging of twin twin transfusion syndrome. JPerinatol1999; 19: Rychik J, Ayres N, Cuneo B, Gotteiner N, Hornberger L, Spevak PJ, Van Der Veld M. American Society of Echocardiography guidelines and standards for performance of the fetal echocardiogram. J Am Soc Echocardiogr 2004; 17: Ichizuka K, Matsuoka R, Hasegawa J, Shirato N, Jimbo M, Otsuki K, Sekizawa A, Farina A, Okai T. The Tei index for evaluation of fetal myocardial performance in sick fetuses. Early Hum Dev 2005; 81: Falkensammer CB, Paul J, Huhta JC. Fetal congestive heart failure: correlation of Tei-index and Cardiovascular-score. J Perinat Med 2001; 29: Rizzo G, Capponi A, Rinaldo D, Arduini D, Romanini C. Ventricular ejection force in growth-retarded fetuses. Ultrasound Obstet Gynecol 1995; 5: Mielke G, Benda N. Cardiac output and central distribution of blood flow in the human fetus. Circulation 2001; 103: Anderson DF, Bissonnette JM, Faber JJ, Thornburg KL. Central shunt flows and pressures in the mature fetal lamb. Am J Physiol 1981; 241: H60 H Reller MD, Morton MJ, Reid DL, Thornburg KL. Fetal lamb ventricles respond differently to filling and arterial pressures and to in utero ventilation. Pediatr Res 1987; 22: Pinson CW, Morton MJ, Thornburg KL. Mild pressure loading alters right ventricular function in fetal sheep. Circ Res 1991; 68: Harkness UF, Crombleholme TM. Twin-twin transfusion syndrome: where do we go from here? Semin Perinatol 2005; 29: Jain V, Fisk NM. The twin twin transfusion syndrome. Clin Obstet Gynecol 2004; 47: Quintero RA. Twin twin transfusion syndrome. Clin Perinatol 2003; 30: Cheung YF, Taylor MJ, Fisk NM, Redington AN, Gardiner HM. Fetal origins of reduced arterial distensibility in the donor twin in twin twin transfusion syndrome. Lancet 2000; 355: Bajoria R, Ward S, Sooranna SR. Influence of vasopressin in the pathogenesis of oligohydramnios polyhydramnios in

7 46 Szwast et al. monochorionic twins. Eur J Obstet Gynecol Reprod Biol 2004; 113: Mahieu-Caputo D, Muller F, Joly D, Gubler MC, Lebidois J, Fermont L, Dumez Y, Dommergues M. Pathogenesis of twin twin transfusion syndrome: the renin angiotensin system hypothesis. Fetal Diagn Ther 2001; 16: Mahieu-Caputo D, Meulemans A, Martinovic J, Gubler MC, Delezoide AL, Muller F, Madelenat P, Fisk NM, Dommergues M. Paradoxic activation of the renin angiotensin system in twin twin transfusion syndrome: an explanation for cardiovascular disturbances in the recipient. Pediatr Res 2005; 58: Mahieu-Caputo D, Dommergues M, Delezoide AL, Lacoste M, Cai Y, Narcy F, Jolly D, Gonzales M, Dumez Y, Gubler MC. Twin-to-twin transfusion syndrome. Role of the fetal renin angiotensin system. Am J Pathol 2000; 156: Kilby MD, Platt C, Whittle MJ, Oxley J, Lindop GB. Renin gene expression in fetal kidneys of pregnancies complicated by twin-twin transfusion syndrome. Pediatr Dev Pathol 2001; 4: