Twin-reversed arterial perfusion sequence: pre- and postoperative cardiovascular findings in the pump twin

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1 Ultrasound Obstet Gynecol 2009; 34: Published online 24 September 2009 in Wiley InterScience ( DOI: /uog.6431 Twin-reversed arterial perfusion sequence: pre- and postoperative cardiovascular findings in the pump twin M. L. KINSEL-ZITER*, J. F. CNOTA*, T. M. CROMBLEHOLME and E. C. MICHELFELDER* *Fetal Heart Program and Fetal Care Center of Cincinnati, Cincinnati Children s Hospital Medical Center, Cincinnati, Ohio, USA KEYWORDS: perfusion cardiac function; cardiac output; fetal echocardiography; radiofrequency ablation; twin-reversed arterial ABSTRACT INTRODUCTION Objectives To assess cardiovascular findings in twinreversed arterial perfusion (TRAP) sequence pre- and post-therapy and compare these findings to traditional obstetric markers, defined as acardius to pump twin weight ratio and presence of polyhydramnios. Methods This was a retrospective review of 27 cases of TRAP sequence diagnosed between 2004 and Echocardiographic data included indexed cardiac output and functional and anatomic parameters. Ultrasound reports were reviewed for acardius to pump twin weight ratio and polyhydramnios. We assessed the relationship between cardiac output and the remaining cardiac/obstetric variables obtained pre- and posttreatment. Results Twenty-three subjects had complete echocardiographic data sets at initial evaluation (mean gestational age, 20.4 ± 2.5 weeks) and, of these, post-treatment echocardiographic evaluation was available in 10. Six of seven (86%) pump twins with elevated indexed cardiac output had significant cardiovascular compromise. Most fetuses with abnormal cardiac output or right ventricular dysfunction normalized post-therapy. There was no relationship between cardiac output and obstetric markers. Conclusions Elevated indexed cardiac output is strongly associated with cardiovascular compromise. Traditional obstetric prognosticators do not correlate with cardiovascular derangements. In pump twins with cardiac compromise, postoperative cardiovascular status improves acutely. Given this analysis, we conclude that assessment of cardiovascular findings should be incorporated into the management and treatment of TRAP sequence. Copyright 2009 ISUOG. Published by John Wiley & Sons, Ltd. Twin-reversed arterial perfusion (TRAP) sequence is a rare and potentially lethal condition affecting approximately 1% of monozygotic twin gestations 1. A normal twin, or pump twin, perfuses its severely malformed cotwin with deoxygenated blood via retrograde flow in direct arterioarterial anastamoses between the umbilical arteries of each twin. The anomalous twin, or acardius, then returns further deoxygenated blood back to the pump twin through a direct venovenous anastamosis. Untreated, pump twin mortality is 50% 1, usually owing to prematurity or high-output cardiac failure. Assessment of disease severity and prognosis in TRAP has historically been characterized by a number of sonographic indicators, including the acardius to pump twin weight (AC : PT) ratio or presence of polyhydramnios 1. Others have described the use of umbilical artery resistance 2 and pulsatility index ratios 3 to assess the hemodynamic burden of the acardius; however, none of these studies attempted to directly relate cardiovascular findings on echocardiography to clinical status. Cardiovascular decompensation in the pump twin is thought to occur as a result of a sustained volume overload due to the perfusion demands placed on it by the acardius. Based upon this hypothesis, radiofrequency ablation (RFA) of the umbilical cord is performed to interrupt blood flow to the acardius, theoretically reducing excess pump twin workload. However, despite the perceived hemodynamic burden in TRAP sequence and the benefits of therapeutic intervention, little data are available to describe the range and degree of cardiovascular findings specific to this condition. The aim of this study was to describe the fetal echocardiographic findings in TRAP, compare these findings with historic indicators of disease severity (AC : PT ratio Correspondence to: Dr E. C. Michelfelder, Fetal Heart Program, Division of Cardiology, Cincinnati Children s Hospital Medical Center, 3333 Burnet Ave., MLC 2003 Cincinnati, OH 45229, USA ( erik.michelfelder@cchmc.org) Accepted: 8 January 2009 Copyright 2009 ISUOG. Published by John Wiley & Sons, Ltd. ORIGINAL PAPER

2 Echo findings in TRAP 551 and polyhydramnios), and examine acute cardiovascular changes following RFA. METHODS Between January 2004 and April 2007, 27 patients with TRAP sequence were referred to the Fetal Care Center of Cincinnati for the purpose of RFA of the acardius. All patients received a fetal echocardiogram for assessment of pump twin cardiac anatomy and function. In 23 patients, complete echocardiographic data sets were available; these subjects constitute the study population. All data collection and storage were done with the approval of the institutional review board and in congruency with the Health Insurance Portability and Accountability Act. Obstetric ultrasound reports were reviewed to ascertain the presence of polyhydramnios and determine the AC : PT ratio. Polyhydramnios was defined as a deepest vertical pocket greater than 6 cm. The pump twin weight was determined by the formula of Hadlock et al. 4. The acardius weight (in grams) was determined by ultrasonography as previously described 1 : weight = ( 1.66 length) + (1.21 length 2 ), where length (in cm) represents the longest linear dimension of the acardius. A high-risk AC : PT ratio was identified as greater than 70%. Reverse flow was confirmed in the acardius s umbilical artery in all cases. All pertinent echocardiographic data were analyzed to obtain a complete cardiovascular assessment prior to RFA. When available, post-rfa echocardiographic data were analyzed to assess for acute changes in cardiovascular status. Ventricular systolic function was assessed by calculation of biventricular shortening fractions by M-mode sonography; normal right and left ventricular shortening fraction was defined as 28% 5. The degree of atrioventricular valve regurgitation was graded semi-quantitatively as mild (narrow jet half the atrial length), moderate (narrow jet > half the atrial length), or severe (wide jet > atrial length) 6. Combined cardiac output was derived through Doppler ultrasound scan of the aortic and pulmonary valves, using the following equation: output through valve = 3.14 valve radius 2 velocity time integral heart rate. The combined (right + left ventricular) cardiac output was then indexed to the estimated fetal weight, known as the combined cardiac index (CCI), and compared to published normal values 7, which range from 225 to 625 ml/min/kg. Morphometric parameters obtained were cardiothoracic area ratio (CTR), cardiac chamber dimensions and ventricular wall thicknesses. A CTR of 0.35 was considered elevated 5. Cardiac chamber and wall dimensions were compared to published gestational age-based normal values 8. Pulsed-wave Doppler evaluation of the umbilical vein and ductus venosus was performed to assess for abnormalities in venous flow. Abnormal venous Doppler was defined as either absent or reversed flow in the ductus venosus during atrial systole, or umbilical venous pulsation in the free umbilical cord. Both obstetric and cardiac ultrasound examinations were performed using Siemens Sequoia (Siemens Medical Solutions, Malvern, PA, USA) or Voluson E8 (GE Healthcare, Milwaukee, WI, USA) ultrasound systems. In all instances, tracings were obtained at an angle of insonation of less than 30 to ensure accurate velocity data. All measurements were performed three times and averaged. The fetal cardiovascular profile score (CVPS) 9 was used as a composite assessment of fetal cardiovascular status for the pump twin. The CVPS utilizes fetal echocardiographic and ultrasound findings to assess fetal cardiovascular state. It consists of a 10-point scale that incorporates the presence or absence of hydrops, abnormal venous and arterial Doppler findings, cardiomegaly, atrioventricular valve regurgitation and cardiac dysfunction. There are 1 2 point deductions from the total score depending on the extent of cardiovascular abnormalities noted (Table 1). Significant cardiovascular compromise was defined as a CVPS 8. Our institution established RFA as its preferred treatment method based upon published data on associated premature delivery rates and clinical success rates 10. Intrafetal RFA was performed under local analgesia and intravenous sedation with a 19-gauge LeVeen needle with 2-cm tines. With ultrasound guidance, the tines deployed completely within the fetal abdomen at the umbilical cord insertion site. RFA was started with 60 W of power for 60 s, and the power was increased by 20-W increments at 60-s intervals to 120 W or when impedance dropped. Cessation of flow within the acardius was confirmed by color Doppler ultrasonography. Patients were observed overnight. Intravenous magnesium sulfate was used as needed following the procedure for tocolysis. No patient received non-steroidal anti-inflammatory drugs that could potentially result in altered hemodynamics. Statistical analysis Correlation analysis was used to assess the relationship between CCI and AC : PT ratio, CTR, and cardiac chamber sizes/wall dimensions. Differences in CCI in pump twins with or without polyhydramnios or elevated AC : PT ratio were compared by Wilcoxon rank-sum test. Changes in cardiovascular function before and after RFA were compared by Wilcoxon signed-rank test or McNemar s test as appropriate. Statistical significance was defined as P < RESULTS Twenty-three subjects had complete echocardiographic data sets at initial evaluation (mean gestational age, 20.4 ± 2.5 weeks). Twenty-one patients subsequently underwent treatment. Two patients did not receive treatment owing to a contraindicated triplet gestation.

3 552 Kinsel-Ziter et al. Table 1 Cardiovascular profile score 9 Parameter Normal (2 points) 1 point 2 points Hydrops fetalis None Ascites, pleural effusion, Skin edema or pericardial effusion Abnormal venous Doppler Normal venous Doppler Ductus venosus atrial systolic reversal Umbilical venous pulsations Cardiomegaly CTR 0.35 CTR > 0.35 and < 0.50 CTR 0.50 Abnormal myocardial function SF > 0.28 and no valve SF < 0.28 or TR or TR plus dysfunction or any MR regurgitation semilunar valve regurgitation Abnormal arterial Doppler Normal umbilical artery Absent end-diastolic flow Reversed end-diastolic flow in diastolic flow in the umbilical artery the umbilical artery CTR, cardiothoracic area ratio; MR, mitral regurgitation; SF, ventricular shortening fraction; TR, tricuspid regurgitation. Of the patients receiving treatment, 20 received RFA. The remaining subject underwent umbilical cord coagulation and release because of monoamniotic gestation with cord entanglement. Comprehensive pre- and post-rfa echocardiographic evaluations were available in nine subjects. The echocardiographic parameters obtained on follow-up examination were identical to those obtained preoperatively. The median time elapsed between preand post-rfa echocardiography was 3 (range, 2 11) days. Preoperative clinical findings in all the subjects are summarized in Table 2. Polyhydramnios was present in 9/23 (39%) of the subjects. An AC : PT ratio of 70% was present in 12/23 (52%) of the subjects. Cardiovascular compromise (CVPS 8) was present in 7/23 (30%) of the subjects; no pump twin had abnormal left ventricular systolic function pre-rfa. There was a highly significant positive correlation between the CCI and CTR (r = 0.81, P < , Figure 1). Six of the seven pump twins with elevated CCI had significant cardiovascular compromise (Figure 1). There was a significant positive correlation between CCI and transverse right atrial dimension (r = 0.67, P < 0.001) and transverse ventricular dimensions (left ventricle: r = 0.57; P < 0.01; right ventricle: r = 0.54; P < 0.01). There was no significant difference in CCI between subjects with or without polyhydramnios (592 ± 147 vs. 559 ± 289 ml/min/kg, P = 0.26) nor with or without a high AC : PT ratio (634± 253 vs. 544 ± 227 ml/min/kg, P = 0.34). There was no significant correlation between CCI and AC : PT ratio. Of 20 subjects undergoing RFA, complete pre- and post-rfa data were available in 10 pump twins (Table 3). There was sudden intrauterine demise of one pump twin with hydrops (CVPS = 5) prior to follow-up imaging. At the discretion of the managing physicians, follow-up fetal echocardiography was not performed in the remaining nine cases. There was no evidence of significant cardiovascular compromise pre-rfa in any of these 10 cases. There was a significant mean difference in CCI (730 ± 266 vs. 535 ± 100 ml/min/kg, P < 0.05) between pre- and post-rfa examinations. There was no significant difference in group means for CTR, left or right ventricular shortening fraction, or in the frequency of atrioventricular valve regurgitation or abnormal ductus venosus or umbilical venous Doppler. Cardiothoracic area ratio Combined cardiac index (ml/min/kg) Figure 1 Cardiothoracic area ratio (CTR) vs. indexed combined cardiac output (CCI) in 23 pump twins with TRAP sequence. The upper limit for CTR (...) and the published normal limits for CCI 7 (vertical lines: , mean value;,5 th and 95 th percentiles) are shown. Amongst pump twins with elevated CCI, six out of seven presented with evidence of significant cardiovascular compromise., subjects with significant cardiovascular compromise;, subjects without cardiovascular compromise. Following RFA, the CVPS was improved or fully normalized in four of six pump twins defined as having significant cardiovascular compromise (CVPS 8) (Figure 2). The two pump twins whose CVPS decreased post-rfa both exhibited umbilical venous pulsations on follow-up ultrasound. One fetus demonstrated moderate constriction of the ductus arteriosus. This infant was also found to have mosaic Turner syndrome postnatally. The second fetus had the highest CCI and lowest CVPS (5) preoperatively, and the acardius s cord was found to have recanalized on subsequent follow-up ultrasound scan. In pump twins with low right ventricular shortening fraction (< 28%), three of four (75%) normalized post- RFA (Figure 3). Among pump twins with abnormally elevated CCI preoperatively (n = 6), three decreased to normal and two to near-normal levels post-rfa (Figure 4). DISCUSSION The current study describes detailed cardiac findings in pump twins with TRAP sequence, and relates these

4 Echo findings in TRAP 553 Table 2 Clinical characteristics of pump twins Subject GA (weeks) CCI (ml/min/kg) Polyhydramnios AC : PT ratio CVPS High CTR AVVR Ventricular dysfunction Abnormal venous Doppler Hydrops 10* * * * * * * *Pump twins with significant cardiac compromise. Not assessed. AC : PT ratio, acardius to pump twin weight ratio; AVVR, atrioventricular valve regurgitation; CCI, indexed combined cardiac output; CTR, cardiothoracic area ratio; CVPS, cardiovascular profile score; GA, gestational age. Table 3 Cardiovascular findings in pump twins pre- and post-radiofrequency ablation GA (weeks) CCI (ml/min/kg) CVPS High CTR AVVR Ventricular dysfunction Abnormal venous Doppler Hydrops Subject Pre Post Pre Post Pre Post Pre Post Pre Post Pre Post Pre Post Pre Post 12* * * * * * *Pump twins with significant preoperative cardiac compromise. AVVR, atrioventricular valve regurgitation; CCI, indexed combined cardiac output; CTR, cardiothoracic area ratio; CVPS, cardiovascular profile score; GA, gestational age. findings to their clinical status as well as to other perhaps more widely used indicators of disease severity such as AT : PT ratio and polyhydramnios. Our data also demonstrate, in a smaller cohort of pumps twins with post-rfa data, the cardiovascular benefit of RFA in the short-term follow-up therapy. To our knowledge, this is the largest study describing comprehensive cardiovascular findings pre- and post-rfa in TRAP sequence to date. The pathophysiology in TRAP sequence consists of arterioarterial and venovenous chorioangiopagus with a pump twin perfusing a severely malformed cotwin with either no, or a very primitive and dysfunctional, heart. This arrangement results in a variable high cardiac output state in the pump twin, which is obligated to provide cardiac output to both its own systemic and placental circulation, as well as the vascular circulation of the acardius. In addition, the venous return of the acardius is added to the pump twin s circulation. Other investigators have attempted to quantify the degree of flow to the acardius by assessment of the relative resistance

5 554 Kinsel-Ziter et al. Cardiovascular profile score Pre-RFA Post-RFA Figure 2 Pre- and post-radiofrequency ablation (RFA) cardiovascular profile score (CVPS) in pump twins. Each patient is represented pre- and postoperatively by an identical symbol. Significant cardiovascular compromise was defined as a CVPS 8 (----). Right ventricular shortening fraction (%) Pre-RFA Post-RFA Figure 3 Pre- and post-radiofrequency ablation (RFA) right ventricular shortening fraction (RVSF) in pump twins. Each patient is represented pre- and postoperatively by an identical symbol. RVSF normalized in three of four pump twins post-rfa , lower limit of normal RVSF. in the umbilical artery of pump twin and acardius 2 or pulsatility index ratios 3. However, we are not aware of prior reports utilizing quantitative echocardiography to assess cardiovascular status in TRAP. The current study demonstrates a direct relationship between CCI, cardiothoracic area ratio, and cardiac morphometric measurements. Our data indicate that increases in global heart size appear to occur as a result of combined atrial and ventricular enlargement. Individual chamber dimensions increase uniformly in direct relation to elevations in cardiac output, a finding indicating excess volume load as the cause in pump twin heart failure. Our data further suggest that elevated CCI is associated with a high incidence of cardiovascular compromise as assessed by CVPS due to the presence of ventricular systolic dysfunction, atrioventricular valve regurgitation, cardiomegaly, hydrops, or abnormal Doppler velocimetry. This makes intuitive sense, as the fetal heart operating at progressively higher outputs would be expected to reach Combined cardiac index (ml/min/kg) Pre-RFA Post-RFA Figure 4 Pre- and post-radiofrequency ablation (RFA) indexed combined cardiac output (CCI) in pump twins. Each patient is represented pre- and postoperatively by an identical symbol. CCI normalized (or nearly normalized) post-rfa in five of six pump twins with preoperative elevation , upper limit of normal for CCI 7. it functional limits. Pathologic elevations in cardiac filling pressure related to ventricular volume loading likely manifest as end-diastolic flow reversals in the ductus venosus and umbilical venous pulsations. It is interesting to note that, in the current study cohort, traditional obstetric prognosticators such as the AC : PT ratio and polyhydramnios 1 did not correlate with cardiovascular derangements. Although an AC : PT ratio > 70% has been associated with a high risk of adverse pregnancy outcome, including premature delivery and rupture of membranes, hydramnios, and fetal heart failure 1 it does not appear to closely reflect the hemodynamic burden placed on the pump twin. Given the poor correlation between AC : PT ratio and CCI, we speculate that identification of pump twins at a higher risk of heart failure may be improved by fetal echocardiography, by detection of elevations in either cardiothoracic area ratio and/or indexed combined cardiac output (Figure 1). It may be clinically useful, for example, to utilize pump twin cardiovascular data for stratification of patients into various treatment strategies, based on the level of suspicion of impending cardiovascular compromise. Specifically, patients with lower pump twin CCI may benefit from expectant management, whereas pump twins with high CCI may benefit from more invasive therapy aimed at acardius cord occlusion. Echocardiography of pump twins following RFA demonstrated that the predominant changes are noted in fetuses with elevated CCI or ventricular dysfunction preoperatively. The inconsequential change noted in the CCI of pump twins that exhibited normal CCI before treatment suggests that the excess workload demanded by the acardius in those pregnancies was not significant. Following RFA of the acardius, acute volume unloading of the pump twin is observed, as evidenced by lower CCI. In addition, post-rfa fetal echocardiography demonstrated that ventricular systolic function has the capability of rapid recovery.

6 Echo findings in TRAP 555 Improvements in compromised fetuses venous Doppler flow patterns also suggest that, in some cases, loading conditions were altered sufficiently to normalize cardiac filling pressures. This study was limited by its retrospective nature and, despite representing a relatively large cohort for a study examining a rare fetal condition, its sample size is modest. There is also a potential referral bias, as all cases were referred to our fetal care center specifically for RFA therapy. Owing to this bias, we were not able to collect serial cardiac data in an untreated population, nor were we able to evaluate fetuses undergoing alternative therapies. In addition, pre- and post-rfa data were not obtained in all cases. These factors may limit the ability to generalize our results. In conclusion, quantitative fetal echocardiography reveals that changes in CCI are associated with a high incidence of cardiovascular compromise. Therefore, our data suggest that fetal echocardiography can play an important adjunctive role in the clinical assessment and stratification for therapy in TRAP sequence. Moreover, many of these cardiovascular derangements normalize following RFA of the acardius umbilical cord. Additional, possibly multicenter, studies should be performed to better define the role of echocardiography in evaluation, therapeutic stratification, and followup of TRAP sequence and to elucidate the cardiac natural history and response to various treatment methods. REFERENCES 1. Moore TR, Gale S, Benirschke K. Perinatal outcome of fortynine pregnancies complicated by acardiac twinning. Am J Obstet Gynecol 1990; 163: Dashe JS, Fernandez CO, Twickler DM. Utility of Doppler velocimetry in predicting outcome in twin reversed-arterial perfusion sequence. Am J Obstet Gynecol 2001; 185: Brassard M, Fouron JC, Leduc L, Grignon A, Proulx F. Prognostic markers in twin pregnancies with an acardiac fetus. Obstet Gynecol 1999; 94: Hadlock FP, Harrist RB, Sharman RS, Deter RL, Park SK. Estimation of fetal weight with the use of head, body, and femur measurements a prospective study. Am J Obstet Gynecol 1985; 151: Huhta JC. Fetal congestive heart failure. Semin Fetal Neonatal Med 2005; 10: Michelfelder E, Gottliebson W, Border W, Kinsel M, Polzin W, Livingston J, Khoury P, Crombleholme T. Early manifestations and spectrum of recipient twin cardiomyopathy in twin twin transfusion syndrome: relation to Quintero stage. Ultrasound Obstet Gynecol 2007; 30: Mielke G, Benda N. Cardiac output and central distribution of blood flow in the human fetus. Circulation 2001; 103: Tan J, Silverman NH, Hoffman JI, Villegas M, Schmidt KG. Cardiac dimensions determined by cross-sectional echocardiography in the normal human fetus from 18 weeks to term. Am J Cardiol 1992; 70: Falkensammer CB, Paul J, Huhta JC. Fetal congestive heart failure: correlation of Tei-index and Cardiovascular-score. JPerinatMed2001; 29: Tan T, Sepulveda W. Acardiac twin: a systematic review of minimally invasive treatment modalities. Ultrasound Obstet Gynecol 2003; 22: