J. J. STIRNEMANN, B. NASR, F. PROULX, M. ESSAOUI and Y. VILLE

Transcription

1 Ultrasound Obstet Gynecol 1; 3: 5 57 Published online in Wiley InterScience ( DOI: 1.1/uog.7713 Evaluation of the CHOP cardiovascular score as a prognostic predictor of outcome in twin twin transfusion syndrome after laser coagulation of placental vessels in a prospective cohort J. J. STIRNEMANN, B. NASR, F. PROULX, M. ESSAOUI and Y. VILLE Department of Obstetrics and Maternal-Fetal Medicine, GHU Necker Enfants Malades, University Paris Descartes, Paris, France KEYWORDS: echocardiography; laser; prognosis; staging; twin twin transfusion syndrome ABSTRACT Objective To investigate the prognostic value of cardiac function assessment by the previously reported CHOP (Children s Hospital of Philadelphia) cardiovascular score in twin twin transfusion syndrome (TTTS). Methods All consecutive monochorionic pregnancies presenting with TTTS over a -month period were evaluated by preoperative echocardiography before percutaneous laser coagulation of chorionic vessels. Each of the 1 items of the was evaluated prospectively and the cardiovascular score was categorized into stages using previously published cutoffs. The outcome considered for this study was neonatal survival of neither, one or both twins. Results In total, 15 pregnancies were enrolled. Due to technical issues, CHOP evaluation was incomplete in 1% of cases and follow-up was unavailable in 1%. Overall, there was a significant relationship between the and the Quintero staging system, although this relationship was significantly reduced when parameters used in the Quintero system were removed from the. Based upon neonatal survival, the did not show any prognostic value regarding overall pregnancy outcome or individual recipient survival. Conclusion Cardiac function assessment using the is not of clinical use as a prognostic marker in TTTS. This suggests that cardiac function may not be of interest for preoperative staging when laser coagulation is the first-line treatment, other than to confirm the diagnosis of TTTS requiring surgery. Copyright 1 ISUOG. Published by John Wiley & Sons, Ltd. INTRODUCTION Although the treatment strategy is one of the strongest determinants of prognosis in twin twin transfusion syndrome (TTTS) 1, preoperative prognostic markers are still desperately lacking. Aside from the universally applied Quintero staging system, research has recently focused on the value of the recipient s cardiac function 3 7, which has led to the development of an independent scoring system based upon echocardiographic and peripheral Doppler findings 5. This scoring system, known as the CHOP (Children s Hospital of Philadelphia) score, is specifically designed to represent the cardiovascular status of the twins and has been shown to correlate with the Quintero staging system 5. While its prognostic value has not yet been investigated, further studies using another scoring system, Shah et al. s fetal cardiovascular profile score (CVPS), have suggested a significant prognostic value of cardiac dysfunction in the recipient. These scoring systems are very similar, both using peripheral Doppler features as well as several intracardiac echocardiographic features of cardiac function. However, the uses a greater number of variables and was designed specifically for TTTS, whereas the CVPS was developed as a generic tool for fetal cardiac function assessment. Our team recently reported a prospective evaluation of recipient cardiac function using unsupervised statistical methods to stage the syndrome-related cardiomyopathy, thus overcoming any arbitrariness of a predefined scoring system 3. However, although we showed that the severity of cardiomyopathy could be assessed successfully using a small number of echocardiographic parameters, we did not find a significant prognostic value of increasing Correspondence to: Prof. Y. Ville, Maternité etmédecine Materno-foetale, Hôpital Necker Enfants Malades, 19 rue de Sevres, 7515 Paris, France ( ville.yves@gmail.com) Accepted: May 1 Copyright 1 ISUOG. Published by John Wiley & Sons, Ltd. ORIGINAL PAPER

2 Prognostic value of in TTTS 53 severity of the recipient s cardiac involvement when treating with percutaneous laser coagulation. The purpose of this study was to evaluate the prognostic value of the in a prospective cohort of monochorionic pregnancies complicated with TTTS and treated by selective percutaneous laser photocoagulation. METHODS All consecutive monochorionic pregnancies complicated with TTTS at our center were evaluated prospectively by echocardiography on admission over a -year period ( ). Inclusion criteria were: twin pregnancy with TTTS defined by a deepest vertical pool (DVP) 1 cm after weeks or cm before weeks, with a distended bladder in the recipient twin; oligohydramnios in the donor defined as DVP cm with small or no bladder 1 ; gestational age between 1 and weeks. Exclusion criteria were: fetal malformations; premature rupture of membranes prior to surgery; amniocentesis prior to surgery. The syndrome was staged according to the Quintero staging system. Pathological examination of the placenta confirmed chorionicity in all cases. Echocardiograms were performed within h prior to surgery and followed a predefined protocol based on the recommendations of the American College of Echocardiography. All measurements were performed using an Aloka ProSound Alpha 1, a GE Voluson 73 or a GE Voluson E ultrasound machine. Pulsed Doppler measurements were performed with an insonation angle < and the mean of three consecutive measurements was used for all quantitative parameters. The CHOP score was computed, using the scoring sheet of Rychik et al. 5, as the sum of 1 cardiovascular parameters (11 in the recipient and one in the donor) scored according to severity (Table 1). The ranges from to and is classified into four CHOP stages: Stage 1 includes scores of 5, Stage includes scores 1, Stage 3 includes scores and Stage includes scores 1. Within h following echocardiography, all patients underwent percutaneous selective laser coagulation of placental vessels 1,9. Briefly, a -mm semi-rigid fetoscope was inserted in the polyhydramniotic cavity using a Seldinger device under local anesthesia and continuous ultrasound guidance. A -µm diode or Yag fiber was used to coagulate the anastomotic vessels as selectively as possible under visual control. The procedure ended with an amniodrainage when no remaining patent anastomoses could be found. In cases with an anterior placenta, a curved shaft was used to access the chorionic surface. Neonatal survival was considered the outcome of interest with which to investigate the prognostic value of the preoperative. The relationship between the and prognosis was evaluated in terms of no, one and two survivors per pregnancy as well as in terms of recipient survival because the score focuses on the recipient s cardiac function. Table 1 Components of the CHOP (Children s Hospital of Philadelphia) score 5 Cardiovascular parameter score Description Recipient Ventricular hypertrophy Interventricular septum < SD 1 > SD Cardiomegaly Cardiothoracic ratio < 1/3 1 > 1/3 and <.5 >.5 Ventricular systolic function Shortening fraction 3% 1 < 3% and > % % MV regurgitation Color flow area of regurgitant jet Absent 1 < 5% atria > 5% atria TV regurgitation Color flow area of regurgitant jet Absent 1 < 5% atria > 5% atria MV EA Merging of E- and A-waves Absent 1 Present TV EA Merging of E- and A-waves Absent 1 Present Ductus venosus End-diastolic A-wave Positive 1 Absent Negative Pulsatile umbilical vein No 1 Yes Pulmonary regurgitation No 1 Yes Right ventricular outflow tract (RVOT) PA > Ao 1 PA = Ao Ao > PA 3 RVOT obstruction Donor Umbilical artery End-diastolic flow Positive 1 Absent Negative Ao, aorta; EA, E- and A-waves on pulsed Doppler interrogation; MV, mitral valve; PA, pulmonary artery; TV, tricuspid valve. Statistical analysis Analyses were performed and graphs produced using R v Quantitative variables are presented using median and interquartile range, and categorical variables using ratios and percentages. The relationship between Quintero and CHOP staging is presented using a bar plot of proportions. distributions across s were compared using the Kruskal Wallis test and subsequently with Wilcoxon s test for pairwise comparisons. The relationship between the number of survivors and prognosis was plotted and tested using Copyright 1 ISUOG. Published by John Wiley & Sons, Ltd. Ultrasound Obstet Gynecol 1; 3: 5 57.

3 5 Stirnemann et al. Fisher s exact test. Since the statistical description of the relationship between a continuous predictor and a dichotomous outcome is not straightforward, a 3-knot natural spline was fitted to smooth the relationship between and recipient survival, providing a non-parametric graphical description of this relationship. RESULTS In total, 15 patients were diagnosed with TTTS over the -year study period. The median gestational age at diagnosis was weeks, with the majority of cases presenting at Quintero Stage III (Table ). Complete cardiovascular evaluation by was performed successfully in 11 (%) cases. The 3 cases with incomplete evaluation (summarized in Table 3) were excluded. Incomplete evaluations were due mainly to technical reasons (polyhydramnios and oligohydramnios causing difficulty in accessing the fetal heart), as well as to maternal discomfort. Pregnancy outcome was not available in 5 (1%) cases because of loss to follow-up. Among the 19 remaining cases (including those with incomplete CHOP evaluation), overall survival was 33% and 55% for one and both twins, respectively, yielding a perinatal survival rate of at least one twin of %. Breaking down survival according to, survival of at least one twin occurred in 5%, 95%, % and 1% of Stage I, II, III and IV cases, respectively. Excluding those lost to follow-up and those with incomplete echocardiographic assessment left 15 pregnancies available for prognostic analysis of the CHOP scoring system. The median was and most cases were CHOP Stage 1 or. None of the cases in this population was diagnosed with CHOP Stage. The most Table Demographic characteristics of 15 pregnancies presenting with twin twin transfusion syndrome Characteristic Value GA at diagnosis (n = 15) (1 + to + 3) (n = 15) I (1) II 31 (1) III 13 () IV () (n = 11) ( ) CHOP stage (n = 11) (7) () 3 (3) () Survival (n = 19) No twins 3 (1) One twin (33) Both twins 15 (55) Donor survival (n = 19) 15 () Recipient survival (n = 19) 17 (77) Data are presented as median (interquartile range) or n (%). Numbers of pregnancies for each characteristic vary because in 3 the CHOP (Children s Hospital of Philadelphia) cardiovascular score evaluation was incomplete and 5 were lost to follow-up. Table 3 Details of CHOP (Children s Hospital of Philadelphia) cardiovascular score evaluation in the study population Cardiovascular parameter score (n = 15) (n (%)) Incomplete CHOP (n = 3) (n (%)) Ventricular hypertrophy 1 (53) 13 () 1 7 (3) Cardiomegaly () 13 (3) 1 5 (31) 1 () Ventricular systolic function 1 (53) 11 (1) 1 51 () 5 (13) MV regurgitation () 19 (91) 1 11 (5) () TV regurgitation 1 (3) 5 (3) 1 77 (3) 7 (3) MV EA () 1 () 1 5 (1) TV EA () 17 (7) 1 () Ductus venosus () 155 (7) 1 3 (1) 3 (1) Pulsatile umbilical vein 1 (3) 15 (5) 1 9 () Pulmonary regurgitation 1 (3) 17 (7) 1 7 (13) Right ventricular outflow 3(9) tract (RVOT) 19 (91) 1 1 () (3) 3 (1) Donor umbilical artery 1 (3) 19 (7) 1 5 () 13 () EA, E- and A-waves on pulsed Doppler interrogation; MV, mitral valve; TV, tricuspid valve. frequently encountered abnormal components were moderate cardiomegaly, ventricular hypertrophy, tricuspid valve regurgitation, a pulsatile umbilical vein, moderate ventricular systolic dysfunction in the recipient twin and abnormal flow patterns in the umbilical artery in the donor twin (Table 3). Inspecting the bar plot in Figure 1, CHOP and Quintero stages showed a similar pattern, with higher Quintero stages having greater proportions of higher CHOP stages. Similarly, the distributions of s across Copyright 1 ISUOG. Published by John Wiley & Sons, Ltd. Ultrasound Obstet Gynecol 1; 3: 5 57.

4 Prognostic value of in TTTS 55 n = 37 n = n = 11 n = I II III IV Figure 1 Comparison between the CHOP (Children s Hospital of Philadelphia) score 5 and the Quintero staging system. Bars present the relative proportion of CHOP Stages 1 ( ), ( )and 3( ) according to. For each, a detailed description of the distribution of s is presented (right-hand side axis); the size of each point is proportional to the observed frequency of s at each. s showed a shift towards higher score values at higher s (Figure 1). However, the components of the regarding peripheral Doppler findings are also used in the Quintero staging system, which may account in part for the similarity that we found between these staging systems. Therefore, the relationship between the two staging systems was also investigated after removal of the following parameters from the : DV, pulsatile UV and donor UA. The distribution of the across Quintero stages before and after excluding these fetal Doppler components of the is presented in Figure. There was little difference evident in between Quintero Stages I and II, with a shift evident for Quintero Stages II, this shift being less prominent after exclusion of the peripheral Doppler components from the CHOP score (compare Figures a and b). When analyzing Quintero Stage III pregnancies according to their individual donor and recipient features, Doppler abnormalities were found in the donor in % of cases and in the recipient in %, whereas 3% displayed both donor and recipient Doppler abnormalities. Figures c and d show the relationship between s and s with Stage III subdivided according to donor and recipient features. Stage III recipient is defined by the presence of Doppler anomalies in the recipient regardless of the Doppler features in the donor; whereas Stage III donor implies normal Doppler findings in the recipient. No difference in was found between Stage III donors and Stage III recipients after removal of Doppler parameters. 1 Although, in the 15 cases in which the prognostic value of the was assessed, the relationship between CHOP stage and twin survival was not significant (Fisher s exact test, P =.), overall survival improved with increasing CHOP stage (Figure 3): rates of dual survival were 5%, % and 3% for CHOP Stages 1, and 3, respectively, whereas corresponding survival rates of one twin were 31%, % and 17%. The recipient s survival also seemed to improve with increasing CHOP score, survival rates being 7%, % and 3% for CHOP Stages 1, and 3, respectively. Figure presents a non-parametric depiction of the relationship between the recipient s survival and the. The smoothed line shows no trend of increasing recipient death rate with increasing. Rather, survival slightly improved with higher CHOP values. Interestingly, the increase in recipient survival with increased was apparently related to a decreasing rate of intrauterine fetal demise across CHOP stages: intrauterine demise rates were 5/11 (1%), 3/3 (%) and / (%) for CHOP Stages 1, and 3, respectively. DISCUSSION The striking features in TTTS of syndrome-related hypertrophic cardiomyopathy in the recipient twin has led to the hypothesis that preoperative prognostic staging and riskstratification would be enhanced by using quantitative echocardiographic findings,,7. Indeed, echocardiography has allowed an accurate description of the spectrum of cardiac involvement in the recipient twin. To date, however, the only widely-used classification of the syndrome is the Quintero staging system, whose prognostic value is debated Although the seems globally correlated with Quintero staging as described initially by Rychik et al. 5, we found it showed no difference between Quintero Stages I and II, suggesting that these stages are very similar. Moreover, a significant part of the increase in the between Quintero Stages II and III was explained by the use of peripheral Doppler findings that are also used in Quintero staging. Nonetheless, with or without peripheral Doppler, the successfully identified Quintero Stage IV cases, with a significantly higher score. Our population exhibited much lower s than did the population used to create the CHOP score 5, as demonstrated by our lack of CHOP Stage cases. This may be explained by earlier diagnosis and referral in our population, with less severe preoperative cardiovascular conditions at the time of diagnosis. This is a potential limitation of our study, despite the prospective recruitment that prevented selection bias. The CHOP scoring system failed to show any significant prognostic value for twin survival. Moreover, in our population, both overall and recipient survival following selective laser coagulation of placental vessels increased with increasing CHOP stage. Focusing on Quintero Copyright 1 ISUOG. Published by John Wiley & Sons, Ltd. Ultrasound Obstet Gynecol 1; 3: 5 57.

5 5 Stirnemann et al. (a) (b) 1 1 I II III IV I II III IV (c) (d) 1 1 I II IIID IIIR IV I II IIID IIIR IV Figure Box-and-whiskers plots showing distribution of CHOP (Children s Hospital of Philadelphia) score 5 according to. The plots on the left (a,c) are the complete, including peripheral Doppler parameters; those on the right (b,d) are s after removal of peripheral Doppler findings. Plots (a and b) show the general Quintero staging system, while (c and d) subdivide Quintero Stage III into Stage III donor (IIID) and Stage III recipient (IIIR). Boxes and internal lines represent 5 th 75 th percentile and median. Whiskers extend to the most extreme data point which is no more than 1.5 times the interquartile range from the box. Small circles represent outliers. *Statistically significant pairwise differences. Stage I cases, we did not find any additional value of the since only a small fraction of cases were CHOP Stage, the majority being CHOP stage 1. Using a different methodology we found similar results regarding the prognostic value of preoperative cardiovascular staging in a smaller sample 3. The lack of prognostic value of preoperative cardiac staging following selective laser coagulation of placental vessels is likely to have several explanations. (1) The mechanisms that lead to intrauterine death are independent from cardiac function in the recipient twin. () Percutaneous fetoscopic laser coagulation, by successfully targeting the anastomoses responsible for the hemodynamic imbalance and its cardiovascular effects, nullifies any subsequent consequence of cardiac dysfunction that would have been observed, had the syndrome been left untreated. Moreover, the impact of laser coagulation is likely to be magnified by improvements to the technique and in the operators skill over time, higher survival rates being achieved as time goes on 1,15. (3) Obstetric and surgical parameters are likely to have a much stronger impact on outcome, overshadowing intrinsic fetal cardiac function as a prognostic marker. () The current means of prenatal exploration of cardiac function by echocardiography does not capture the true nature of cardiovascular consequences of the syndrome within the current understanding of the disease. Considering the amount of hope generated by a new potential prognostic factor in TTTS, these results may appear somewhat disappointing. Nonetheless, these results may give insight to help in understanding the syndrome and for future work. Since prognostic assessment would appear to be unrelated to preoperative echocardiographic assessment, research into prognosis might benefit from focussing on different aspects of Copyright 1 ISUOG. Published by John Wiley & Sons, Ltd. Ultrasound Obstet Gynecol 1; 3: 5 57.

6 Prognostic value of in TTTS 57 Proportion n = 11 n = 3 n = 1 3 CHOP stage Figure 3 Relative proportions of survival of neither ( ), one ( ) and both ( ) surviving twins in each of the CHOP (Children s Hospital of Philadelphia) score 5 stages. Death Survival Recipient survival Figure Recipient survival according to CHOP (Children s Hospital of Philadelphia) score 5. For each pregnancy, the recipient s outcome (death/survival) is plotted according to its. This relationship was regressed using a 3-knot natural spline smoother, yielding a non-parametric visual interpretation of the relationship between the recipient s outcome and the. the disease such as obstetric factors and indications for and improvements of the surgical technique, as well as postoperative management. Furthermore, prognosis may not be the only potential application of cardiac function assessment in TTTS, and future studies should focus on its value for the early diagnosis of TTTS 1,17 and cardiac physiology, since the syndrome offers a unique example of fetal cardiovascular stress. REFERENCES 1. Senat M, Deprest J, Boulvain M, Paupe A, Winer N, Ville Y. Endoscopic laser surgery versus serial amnioreduction for severe twin-to-twin transfusion syndrome. NEnglJMed; 351: Quintero RA, Morales WJ, Allen MH, Bornick PW, Johnson PK, Kruger M. Staging of twin-twin transfusion syndrome. JPerinatol1999; 19: Stirnemann JJ, Mougeot M, Proulx F, Nasr B, Essaoui M, Fouron JC, Ville Y. Profiling fetal cardiac function in twintwin transfusion syndrome. Ultrasound Obstet Gynecol 1; 35: Shah AD, Border WL, Crombleholme TM, Michelfelder EC. Initial fetal cardiovascular profile score predicts recipient twin outcome in twin-twin transfusion syndrome. JAmSoc Echocardiogr ; 1: Rychik J, Tian Z, Bebbington M, Xu F, McCann M, Mann S, Wilson RD, Johnson MP. The twin-twin transfusion syndrome: spectrum of cardiovascular abnormality and development of a cardiovascular score to assess severity of disease. Am J Obstet Gynecol 7; 197: 39.e1 39.e.. 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. Ultrasound Obstet Gynecol 7; 3: Barrea C, Hornberger LK, Alkazaleh F, McCrindle BW, Roberts A, Berezovska O, Windrim R, Seaward PG, Smallhorn JF, Ryan G. Impact of selective laser ablation of placental anastomoses on the cardiovascular pathology of the recipient twin in severe twin-twin transfusion syndrome. Am J Obstet Gynecol ; 195: 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 ; 17: Ville Y, Hyett J, Hecher K, Nicolaides K. Preliminary experience with endoscopic laser surgery for severe twin-twin transfusion syndrome. NEnglJMed1995; 33: Taylor MJO, Govender L, Jolly M, Wee L, Fisk NM. Validation of the Quintero staging system for twin-twin transfusion syndrome. Obstet Gynecol ; 1: Quintero RA, Dickinson JE, Morales WJ, Bornick PW, Bermúdez C, Cincotta R, Chan FY, Allen MH. Stage-based treatment of twin-twin transfusion syndrome. Am J Obstet Gynecol 3; 1: Huber A, Diehl W, Bregenzer T, Hackelöer B, Hecher K. Stagerelated outcome in twin-twin transfusion syndrome treated by fetoscopic laser coagulation. Obstet Gynecol ; 1: Stirnemann JJ, Nasr B, Quarello E, Ortqvist L, Nassar M, Bernard J, Ville Y. A definition of selectivity in laser coagulation of chorionic plate anastomoses in twin-to-twin transfusion syndrome and its relationship to perinatal outcome. Am J Obstet Gynecol ; 19:.e1.e. 15. Quintero RA, Comas C, Bornick PW, Allen MH, Kruger M. Selective versus non-selective laser photocoagulation of placental vessels in twin-to-twin transfusion syndrome. Ultrasound Obstet Gynecol ; 1: Raboisson MJ, Fouron JC, Lamoureux J, Leduc L, Grignon A, Proulx F, Gamache S. Early intertwin differences in myocardial performance during the twin-to-twin transfusion syndrome. Circulation ; 11: Lachapelle MF, Leduc L, Côté JM, Grignon A, Fouron JC. Potential value of fetal echocardiography in the differential diagnosis of twin pregnancy with presence of polyhydramniosoligohydramnios syndrome. Am J Obstet Gynecol 1997; 177: Copyright 1 ISUOG. Published by John Wiley & Sons, Ltd. Ultrasound Obstet Gynecol 1; 3: 5 57.