Review Article
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Fetal Echocardiography in Twin–Twin Transfusion Syndrome Anita J. Moon-Grady, MD, FAAP, FACC, FASE1 1 Division of Cardiology, Department of Pediatrics and Fetal Treatment
Center, University of California San Francisco Benioff Children’s Hospital, San Francisco, California
Address for correspondence Anita J. Moon-Grady, MD, FAAP, FACC, FASE, Fetal Cardiovascular Program, 505 Parnassus Ave Box 0214, San Francisco, CA 94143 (e-mail: [email protected]).
Abstract
Keywords
► fetal echocardiography ► cardiomyopathy ► myocardial mechanics
Twin–twin transfusion syndrome is a complex disease process affecting monochorionic twin pregnancies that has implications for the cardiovascular system in both recipient and donor cotwins. Systolic, diastolic, and structural cardiac changes can occur; these have been the subject of intense study over the past two decades, and the use of echocardiography in evaluation of these pregnancies has become common in centers offering treatment of the condition. The role of echocardiography, the clinical cardiovascular and hemodynamic findings characteristic of the syndrome, and proposed pathophysiologic mechanisms and consequences are discussed in this review. Emerging technologies will be presented along with proposed areas for future research.
Twin–twin transfusion syndrome (TTTS) is a complication affecting monochorionic, diamniotic (MCDA) pregnancies at a rate of approximately 10 to 15%. The clinical diagnosis of TTTS is made sonographically by the presence of concurrent polyhydramnios (maximum vertical pocket 8 cm) in the recipient and oligohydramnios (2 cm) in the donor twin. Also seen to varying degrees are cardiac/hemodynamic changes in the recipient twin; donor twins, though less well studied, do not appear to exhibit deleterious functional abnormalities in utero in any of the studies published to date. The pathophysiology of the syndrome and of the development of cardiac involvement in the recipient remains incompletely understood. It has been postulated that abnormal or imbalanced vascular connections in the shared placenta may lead to chronic hypovolemia in the donor and volume overload in the recipient, which in combination with exposure to abnormal vasoactive mediators results in cardiac hypertrophy and cardiomegaly,1–4 with cardiac dysfunction (and ultimately hydrops). These cardiac changes are distinctly different, however, from those induced solely by volume overload or high-output states that lead to heart failure and hydrops, such as those seen in twin-reversed arterial perfusion or sacro-
coccygeal teratoma, in which cardiomegaly without hypertrophy precedes development of hydrops.5 Moreover, though all monochorionic twins including those with TTTS are at baseline at increased risk for congenital heart lesions including septal defects and more complex lesions,6,7 development of acquired structural heart disease can be seen in association specifically with TTTS, including pulmonary valve obstruction and mitral and tricuspid valve lesions.8–10 Treatment of TTTS with selective fetoscopic laser photocoagulation or serial amnioreduction has dramatically improved survival and outcomes in affected pregnancies,2,11 and laser treatment has been shown to significantly improve cardiovascular pathology seen antenatally in the recipient fetus.10,12 In this review, the types of cardiac changes that occur, proposed mechanisms, and methods for detection via echocardiography will be discussed. Ways in which the echocardiographic evaluation can complement the sonographic and the clinical evaluation and management of these pregnancies will be discussed; the role of echocardiography in short- and long-term prognostication and follow-up will be reviewed. Finally, newer methods and emerging technologies with their potential application to evaluation of this intriguing, evolving
received April 6, 2014 accepted April 18, 2014 published online June 10, 2014
Copyright © 2014 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662.
DOI http://dx.doi.org/ 10.1055/s-0034-1378146. ISSN 0735-1631.
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Am J Perinatol 2014;31:S31–S38.
Fetal Echocardiography in Twin–Twin Transfusion Syndrome disease process will be presented along with proposed areas for future research.
Pathophysiologic Considerations in the TTTS “Cardiomyopathy” In 2007, investigators participating in National Institute of Child Health and Human Development (NICHD)–funded North American trial of selective laser photocoagulation of placental anastomoses versus management with amnioreduction alone published a report of their findings.13 Although this trial, which was stopped before the planned sample size had been enrolled, was inconclusive with regard to superiority of laser therapy, subgroup analysis revealed a trend toward worse outcomes in recipient fetuses with preoperative cardiomyopathic changes including tricuspid and mitral regurgitation. The authors concluded that TTTS “cardiomyopathy” appeared to be an important determinant of survival in recipient twins. These findings were similar to those reported in a nonrandomized sample from a single institution.14 Interestingly, the pathophysiology of TTTS cardiomyopathy is less well understood than are the consequences for the fetus. Hypertrophy and hyperplasia, with increased heart weight, are common, even at earlier stages of disease15; tricuspid and mitral regurgitation and declining systolic function are seen particularly in the more advanced stages but are not universal. Several groups have shown that biomarkers associated with “heart failure” are elevated in the amniotic fluid of the recipient, including b-type natriuretic peptide4 as are certain vasoactive mediators including endothelin-1, and there is evidence for abnormal activation of the renin–angiotensin system.1,3 Exposure to these mediators, which result in increased afterload in the recipient, in combination with altered preload, may be the key feature in producing the systolic and diastolic cardiac pathology detected by echocardiography in fetuses at all stages of the disease. Less well understood is the acquisition of fibrotic and proliferative changes that affect the valves, particularly the pulmonary valve, and the endomyocardium of some of these fetuses.16
Role of Echocardiography in Prediction of Development/Progression of TTTS The most widely accepted means of describing the sonographic findings in established TTTS is the Quintero staging system.17 In stage I disease, only polyhydramnios and oligohydramnios are seen; in stage II, with worsened oliguria in the donor, the bladder is no longer seen; in stage III, Doppler abnormalities in the donor umbilical artery and/or the recipient ductus venosus are typically seen; and in stage IV hydropic changes are noted in one twin. The system is meant to be descriptive, and unfortunately pregnancies do not progress through stages in a predictable manner. Furthermore, since TTTS affects a minority of at-risk pregnancies, a tool capable of predicting the development of the condition would be quite useful and could potentially decrease the amount of screening done for unaffected pregnancies. American Journal of Perinatology
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Moon-Grady The twin pairs are usually normal in first trimester but may start to develop discordant fluid in the early second trimester; however, many of those pregnancies that develop discordant fetal size or fluid will not progress to true TTTS, or if they do develop Quintero stage I disease, up to 70 to 85% will not progress further.18–20 Once disease is stage II, nearly half can be expected to worsen, and at stages III and IV progression to severe disease resulting in the demise of one or both twins is almost universal—untreated, overall survival of advanced disease presenting < 26 weeks is only approximately 10 to 20%. Ideally, then, we would be able detect the MC gestation at risk for the development of TTTS that would require more intensive monitoring. In addition, we would want to have a reliable tool for the prediction of stable disease that might be managed expectantly versus disease at risk of progression. The issues surrounding progression of disease from stage I are complex and have been addressed in many forums. Until the results of a current trial randomizing patients with stage I disease to invasive therapy versus expectant management are available, there will be some debate how to optimally manage these pregnancies. Rossi and D’Addario20 published a systematic review of the literature as related to treatment modality for patients presenting with stage I TTTS. The authors found that laser therapy did not confer a survival advantage over conservative management overall, but also that when laser therapy was used as a primary therapy versus a secondary therapy after progression (while undergoing observation), it also did not prove advantageous. Survival was the same whether laser was first-line or “rescue” therapy. Given the apparent limitations of ultrasound staging in predicting disease progression, echocardiography may be an ideal tool for providing more detailed information about the cardiac status of the recipient fetus in pre-TTTS and early-stage TTTS pregnancies.
Echocardiography in Differentiating TTTS from Other Causes of Discordance in MCDA Twins In an early report looking at intertwin differences in timing intervals, as determined by pulsed-wave Doppler interrogation of ventricular inflow and outflow, known to lengthen with varying degrees of systolic (isovolumic contraction time) and diastolic (isovolumic relaxation time [IVRT]) cardiac dysfunction, Raboisson et al21 evaluated 23 TTTS cases and 11 twin pairs with selective intrauterine growth restriction in one twin. They reported an intertwin difference in both right and left ventricular IVRTs only in the pairs affected by TTTS. Several years later, Michelfelder et al22 reported that the right ventricular myocardial performance index or “MPI”(►Fig. 1) —a global measure of cardiac dysfunction encompassing alterations in both systole and diastole—was increased above normal in the majority of recipient twins across all Quintero stages of disease. Therefore, though apparently specific and somewhat sensitive for detection of the myopathic change in TTTS, these measures do not seem sensitive or specific enough for the detection of early disease. Recently, it has been shown that using a combination of tricuspid inflow duration (shortened in diastolic dysfunction and elevated afterload, ►Fig. 2) with IVRT and additional venous Doppler
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Fig. 1 Schematic to show measurement of isovolumic time intervals and calculation of MPI. The tracing is obtained using spectral Doppler, with atrioventricular (tricuspid or mitral) valve inflow in this example shown above and ventricular outflow below. IVCT, isovolumic contraction time; IVRT, isovolumic relaxation time; MPI, myocardial performance index.
parameters for detection of elevation in right atrial pressure (ductus venosus and systemic venous “a” wave velocity, ►Fig. 2), a pattern of early changes can be identified, which is present in recipient fetuses with stages I and II disease and that distinguishes them from twin pairs who do not have or develop disease. These patterns were also present in all of the fetuses in this series who progressed during observation, including those who did not have TTTS at the initial evaluation.23 This single-center experience supported earlier work and suggested that pregnancies at risk for developing TTTS should be evaluated by echocardiography. Further, it suggested that echocardiography may define a “prestage I” in MCDA pregnancies with discordant growth or discordant fluid before the detection of the polyhydramnios/ oligohydramnios that defines TTTS.
Echocardiography in Further Stratifying TTTS at Different Quintero Stages and in Prediction of Outcome The concept of development of a “profile” of cardiac findings that might help differentiate fetuses with TTTS of differing severity and prognosis has been extensively investigated. One method used is the cardiovascular profile score (CVPS) first proposed by Hofstaetter et al.24 The CVPS incorporates evaluation of fetal cardiac systolic function, cardiomegaly, the presence or absence of venous or arterial Doppler abnormalities, and the presence or absence of hydropic changes, generating a composite score of 0 to 10. Shah et al14 adapted the CVPS to TTTS pregnancies and reported on 62 twin gestations, finding that recipient twin survival was greater (50%) for those with a CVPS of 9 and 74% for a CVPS of 10. Furthermore, they found that among the components of the CVPS, atrioventricular valve regurgitation was associated with adverse recipient outcome.
Moon-Grady
Recently, Stirneman et al25 reported 63 cases evaluated before laser with complete echocardiographic data, and applied a multivariate description of the recipient’s cardiac function. Fifty-five percent of the stage I recipients had abnormal cardiac profiles at preoperative assessment in this series. Three different preoperative cardiac profiles were identified consisting of increasing right and left MPI, decreasing right and left shortening fraction, and increasing ductus venosus pulsatility index. The three retrospective group assignments represented progressive stages of TTTSrelated cardiomyopathy, though disappointingly no correlation was found with pregnancy outcome. The group from Cincinnati recently reported the results of a retrospective analysis of 123 pregnancies staged by Quintero staging and by the “Cincinnati Staging”8 algorithm, which incorporates echocardiographic variables previously discussed (►Table 1).18 The study group comprised 77 stage I and 46 stage II pregnancies. Overall the investigators saw a 56% rate of progression among Quintero stages I and II patients (two-thirds were stage I), with increasing relative risk of disease progression in higher Cincinnati stages (50% of Cincinnati stage IIIA, 100% of IIIB, and 67% of IIIC vs. only 40% of stages I and II that were not “upstaged” for cardiac changes) (►Fig. 3). The program at The Children’s Hospital of Philadelphia (CHOP) has published a method for systematically assessing echocardiographic data in TTTS pregnancies.26 The so-called “CHOP score” incorporates both donor (umbilical artery Doppler) and recipient assessments; the score is weighted toward recipient findings, with evaluation for the presence of cardiac hypertrophy, dilation, impaired systolic or diastolic function, atrioventricular valve regurgitation, pulmonary valve structural or Doppler abnormalities, and venous Doppler abnormalities. A composite score of 0 to 20 is generated, with “0” representing the best possible score and “20” being severely affected (►Table 2). Though initially reported as a descriptive score, attempts have been made to apply the CHOP score to prognostication, with disappointing results. Specifically, Stirnemann et al applied the CHOP score retrospectively to 158 pregnancies, all with TTTS27; survival of at least one twin occurred in 85, 95, 84, and 100% of Quintero stages I, II, III, and IV cases, respectively. In this report, CHOP scoring correlated with Quintero stage, but not with survival. Unfortunately, there were only a few fetuses in the worst categories (CHOP score > 10) in this series, limiting the conclusions that can be drawn about stratification using the CHOP score in fetuses with moderate to severe compromise. In summary, the “take-home” at present regarding echocardiographic assessment at presentation and “profiling” in TTTS is disappointing. Although it is still unclear that isolated polyhydramnios/oligohydramnios (stage I) needs treatment, these pregnancies should be monitored for progression with both echo and ultrasound. Echo parameters can be abnormal at all “stages” of TTTS even before diagnosis. These pregnancies should probably be even more closely monitored as echo abnormalities (moderate þ recipient cardiomyopathy) are predictive of progression from Quintero stage I to higher American Journal of Perinatology
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Fetal Echocardiography in Twin–Twin Transfusion Syndrome
Fetal Echocardiography in Twin–Twin Transfusion Syndrome
Moon-Grady
Fig. 2 Doppler indices of ventricular diastolic function evaluated in suspected twin–twin transfusion syndrome. The different Doppler parameters that were used to evaluate diastolic function in the recipient twin are illustrated. Doppler abnormality is defined as the presence of any one of the following: markedly fused or monophasic tricuspid inflow Doppler (upper panels), ductus venosus Doppler pattern S:a ratio > 3:1 (middle left panel), inferior vena cava flow reversal velocity-time integral (VTI) greater than 20% of forward flow velocity time integral (middle right panel), or abnormal umbilical venous flow (lower left panel). In addition, left ventricular isovolumic relaxation time is measured as shown (lower right panel) and compared with normal ranges established on an individual center basis. (Adapted with permission from Moon-Grady et al23.)
stages but not sensitive enough to predict progression in all pregnancies. Current profiling schemes are not useful for predicting pregnancy outcome after laser therapy or for prognosticating at higher (III, IV) Quintero stages. Clearly more study and experience is needed in this area.
Evolution of Cardiomyopathy and Acquired Valvar Dysplasias in TTTS There is an abundance of evidence that the appearance of the recipient cardiomyopathy largely resolves with delivery or
Table 1 Cincinnati staging scheme for twin–twin transfusion syndrome Stage
I
II
IIIA
IIIB
IIIC
III
IV
V
Donor
Oligo
þBladder not seen
Oligo
Oligo
Oligo
þAbnormal UA Doppler
Hydrops in one cotwin
Death of one cotwin
Recipient
Poly
Poly
Poly
Poly
Poly
þAbnormal DV Doppler
Hydrops in one cotwin
Death of one cotwin
None
None
Mild
Moderate
Severe
n/a
n/a
n/a
None
None
2–3 Z-score
3–4 Z-score
> 4 Z-score
n/a
n/a
n/a
None
None
2–3 Z-score
3–4 Z-score
Severe biventricular dysfunction
n/a
n/a
n/a
AVV regurgitation Ventricular hypertrophy MPI
Abbreviations: AVV, atrioventricular (tricuspid and/or mitral) valve; DV, ductus venosus; MPI, myocardial performance index; n/a, not applicable; Oligo, oligohydramnios (deepest vertical pocket /¼ 8 cm); UA, umbilical artery. Source: Adapted with permission from Habli et al.8 American Journal of Perinatology
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Fig. 3 Progression among twin–twin transfusion syndrome patients (Quintero stages I and II) as a function of recipient cardiomyopathy at presentation. Cincinnati stage IIIA, mild cardiomyopathy; Cincinnati stage IIIB, moderate cardiomyopathy; Cincinnati stage IIIC, severe cardiomyopathy. White denotes progression, gray no progression. (Reprinted with permission from Habli et al. 18)
laser therapy, and does so within weeks to months.10,12,28 Less well studied, however, are the potentially more permanent abnormalities of diastolic function and arterial distensibility that have been reported and have been proposed along the lines of the “Barker hypothesis” to be potential fetal origins of adult disease in these patients. Indeed, as early as the 1960s, Naeye reported histologic evidence of abnormal systemic arterial development in affected twins.15 In a single study evaluating arterial distensibility in infant (median age, 9 months) TTTS donor survivors, Cheung et al reported persistent abnormalities of arterial distensibility29 versus control twins. Affecting a minority of recipient twins, but with more clear postnatal consequences, are acquired valvar dysplasias. Most often seen and therefore most well described are right ventricular outflow tract obstructive lesions, valvar pulmonary stenosis, and atresia. Affecting approximately 11% of recipient twins in the prelaser era,16 laser therapy appears to decrease the incidence without totally eliminating it,10 suggesting that the valvar thickening and fibrosis seen histologically may be reversible in some fetuses. Interestingly, in singleton fetuses with pulmonary outflow obstruction, it is known that the ductus venosus “a” wave reversal is seen in up to 45% of mid-gestation fetuses without other evidence of compromise.30 Therefore, a careful assessment by echocardiography is necessary when ductus venosus “a” wave reversal is present, given it will heavily weight Quintero staging toward more “severe” (stage III þ ) disease when fetal compromise may or may not actually be present.
Moon-Grady
Less well described are acquired lesions of the tricuspid and mitral valves. In 2010, Losada et al9 reported for the first time an acquired structural abnormality of the mitral valve (“mitral arcade”) resulting in moderate to severe mitral regurgitation in the recipient twin and suggested that in stage III or IV disease, this finding may portend a particularly poor outcome. Given that 11 to 13% of TTTS recipients may have mitral regurgitation on echocardiogram,13,26 it is possible that evaluation for mitral disease may allow further stratification of these higher Quintero stage pregnancies. Indeed, what little data we have from the NICHD trial13 suggests, on post hoc analysis, that atrioventricular valve regurgitation may be an independent predictor of death. The hemodynamic implication of this finding proposes an interesting discussion. In the fetus with compromised right ventricular output, the left ventricle must compensate. What, then, is the effect of mitral regurgitation, compromised left ventricular filling, or myocardial fibrosis/cardiomyopathy on the ability of that ventricle to provide adequate output and oxygen delivery to the developing fetus? The effect of acquired mitral valve dysplasia in the setting of TTTS is an intriguing question that still has not been answered. Whether this acquired valvar dysplasia, like the pulmonary valve changes, can regress with laser therapy or delivery of the fetus is currently unknown. In summary, with respect to acquired heart disease in TTTS, hypertrophy and diastolic dysfunction in the recipient twin may be the tip of the iceberg in a systemic disease that affects both cotwins. In obstetric evaluation, standard (umbilical artery, ductus venosus) Doppler parameters need to be interpreted carefully and in the context of cardiac pathology especially right ventricular outflow tract obstruction. It has been demonstrated that very poor cardiac status leads to worse outcomes even with adequate therapy. There may be a plausible mechanism to explain this observation if left heart abnormalities accompany right-sided obstruction and/or failure. Echocardiography evaluation both before and after therapy will lead to better risk assessment not only for death but also for short- and long-term cardiac morbidity especially in the subset of patients with more severe/advanced disease at presentation.
Emerging Technologies Maturational and structural differences give rise to observed differences in cardiac function between fetal and postnatal life. Traditional M-mode, grayscale two-dimensional, and Doppler blood flow techniques discussed in this article give indirect insight into myocardial function and its interaction with the vasculature. Recently, several new indices derived from echocardiographic Doppler and tissue Doppler measurements have been proposed as noninvasive measures of systolic and diastolic dysfunction. Measurement of myocardial strain and strain rate using algorithms to track individual regional myocardial mechanics has been applied to several postnatal/adult disease states and to normal fetuses in a handful of recent publications. In the recipient twin in TTTS where there is evolution of ventricular hypertrophy, diastolic American Journal of Perinatology
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Fetal Echocardiography in Twin–Twin Transfusion Syndrome
Fetal Echocardiography in Twin–Twin Transfusion Syndrome
Moon-Grady
Table 2 Cardiovascular parameters used in The Children’s Hospital of Philadelphia scoring scheme Echocardiographic parameter
Score assigned
2D ventricular assessment Cardiomegalya Systolic dysfunction Hypertrophy
b
c
None (0)
Mild (1)
> Mild (2)
None (0)
Mild (1)
> Mild (2)
None (0)
Present (1)
Color Doppler AV valve assessmentd Tricuspid regurgitation
None (0)
Mild (1)
> Mild (2)
Mitral regurgitation
None (0)
Mild (1)
> Mild (2)
2 peaks (normal) (0)
Monophasic/fused (1)
2 peaks (normal) (0)
Monophasic/fused (1)
Spectral (PW) Doppler Tricuspid inflow Mitral inflow Ductus venosus “a” wave
e
Umbilical venous pulsations
All forward (0)
Decreased (1)
None (0)
Present (1)
Reversed (2)
Great vessel assessment 2D outflow tractsf
PA > Ao (0)
PA ¼ Ao (1)
PA < Ao (2)
Color Doppler
Forward flow, no pulmonary regurgitation (0)
Forward flow, pulmonary regurgitation seen (1)
RV outflow tract obstruction, revered ductal flow (3)
Normal (0)
“Decreased” diastolic flow (1)
Absent or reversed diastolic flow (2)
Donor assessment Umbilical artery Doppler
Abbreviations: Ao, aorta; AV, atrioventricular; PA, pulmonary artery; PW, pulsed-wave; RV, right ventricular; 2D, two-dimensional. Source: Adapted with permission from Rychik et al.26 a Cardiac size determined by cardiothoracic ratio by area method: Normal < 0.33, mild cardiomegaly 0.33–0.5, > mild cardiomegaly > 0.5. b Systolic dysfunction is assessed via qualitative assessment of ventricular function or shortening fraction with mild dysfunction 25–30%, > mild dysfunction < 25%. c Ventricular hypertrophy is assessed as present or absent based on qualitative assessment or right ventricular free wall > þ 2 Z-score for gestational age. d Atrioventricular valvar regurgitation is graded via color Doppler imaging of ratio of regurgitant jet area-to-atrial area; < 25% ¼ mild, > 25% ¼ > mild regurgitation. e Ductus venosus flow: atrial contraction velocity < 1/3 peak systolic velocity ¼ “mild” decrease. f Outflow tracts measurements are made at the semilunar valve annular level.
and eventual systolic dysfunction, right and left ventricular strain have been shown to be decreased.31–33 This is possibly related to alterations in afterload or due to myocardial hypertrophy, either of which may have the effect of decreasing tissue deformation. Rychik et al studied 25 pregnancies31 and demonstrated that recipient systolic strain rate and diastolic strain rate were significantly lower for both left and right ventricles in comparison to controls. The donor left ventricular systolic strain rate was higher and right ventricular diastolic strain rate was significantly lower than controls. In general, the feasibility of fetal strain measurement seems reasonable, though several studies report up to 20 to 30% interobserver variability and there are problems with application to individual fetuses and to disease states given the very wide confidence intervals reported in these studies.32,34 Taylor-Clarke et al have recently published data regarding an alteration of the technique to tighten the variability and have applied this methodology to TTTS with success.35 In a recent report comparing TTTS pregnancies with control unaffected twin pairs, they found that recipient American Journal of Perinatology
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left ventricular strain was reduced at all Quintero stages, while recipient right ventricular strain was reduced only in Quintero stages III and IV. Within-pair and between-ventricle values of strain in MCDA twin pairs without TTTS were similar. Left ventricular strain was reduced from early-stage TTTS in recipients but not donor cotwins. Strain improved at a median of 2 weeks following successful laser therapy. Study of TTTS using newer and more specific measures of myocardial mechanics stands to provide further insight into the pathophysiology of fetal myocardial disease and may help with prediction of prognosis as well as in guiding therapy. They may indeed contribute critically to the understanding of the evolution of normal and abnormal mechanics in the human heart and fetal cardiac adaptation to disease.
Summary and Recommendations TTTS produces an acquired cardiomyopathy in “recipient” twins in MC/DA pregnancies that is only partially understood but that can be identified and characterized using fetal echocardiography. The cardiomyopathy, as well as survival
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and neurologic outcomes, is improved with currently available laser therapy techniques. The optimal timing of intervention is yet to be determined and there may be a role for echocardiography in early detection/surveillance in the care of these patients. The role of echo in risk stratification is as yet unclear, but many advances have been made in the last decade. Postlaser and postnatal follow-up echocardiography and cardiac evaluation are recommended for both structural disease and long-term sequelae of cardiomyopathy and vasculopathy induced by the syndrome. Echo evaluation as part of routine ultrasound evaluation (early second trimester), and then as often as every 1 to 2 weeks during observation of affected pregnancies is warranted. When invasive therapy is performed, our current practice includes at a minimum follow-up cardiac evaluation at 24 hours, 1 week, and approximately 1 month after laser therapy. Consideration should be given to detailed postnatal cardiac evaluation in infancy for all survivors (donors and recipients) given the increased rates of both valvar dysplasias and what may initially be clinically silent disease as atrial septal defects, coarctation, patent ductus arteriosus are all increased in incidence in MCDA twins.7 Finally, coordinated efforts to further study known and emerging cardiac parameters in a systematic, multi-institutional collaborative setting is clearly needed to best determine the future role of echocardiography in the diagnosis and treatment of TTTS.
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12
13
14
15 16
17
18
19
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endothelin-1 in the pathogenesis of polyhydramnios-oligohydramnios in monochorionic twins. Am J Obstet Gynecol 2003; 189(1):189–194 Hecher K, Plath H, Bregenzer T, Hansmann M, Hackelöer BJ. Endoscopic laser surgery versus serial amniocenteses in the treatment of severe twin-twin transfusion syndrome. Am J Obstet Gynecol 1999;180(3 Pt 1):717–724 Mahieu-Caputo D, Muller F, Joly D, et al. Pathogenesis of twin-twin transfusion syndrome: the renin-angiotensin system hypothesis. Fetal Diagn Ther 2001;16(4):241–244 Van Mieghem T, Doné E, Gucciardo L, et al. Amniotic fluid markers of fetal cardiac dysfunction in twin-to-twin transfusion syndrome. Am J Obstet Gynecol 2010;202(1):e1–e7 Byrne FA, Lee H, Kipps AK, Brook MM, Moon-Grady AJ. Echocardiographic risk stratification of fetuses with sacrococcygeal teratoma and twin-reversed arterial perfusion. Fetal Diagn Ther 2011; 30(4):280–288 Pettit KE, Merchant M, Machin GA, Tacy TA, Norton ME. Congenital heart defects in a large, unselected cohort of monochorionic twins. J Perinatol 2013;33(6):457–461 Pruetz JD, Sklansky M, Detterich J, Korst LM, Llanes A, Chmait RH. Twin-twin transfusion syndrome treated with laser surgery: postnatal prevalence of congenital heart disease in surviving recipients and donors. Prenat Diagn 2011;31(10):973–977 Habli M, Lim FY, Crombleholme T. Twin-to-twin transfusion syndrome: a comprehensive update. Clin Perinatol 2009;36(2): 391–416, x Losada E, Moon-Grady AJ, Strohsnitter WC, Wu D, Ursell PC. Anomalous mitral arcade in twin-twin transfusion syndrome. Circulation 2010;122(15):1456–1463 Moon-Grady AJ, Rand L, Lemley B, Gosnell K, Hornberger LK, Lee H. Effect of selective fetoscopic laser photocoagulation therapy for
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twin-twin transfusion syndrome on pulmonary valve pathology in recipient twins. Ultrasound Obstet Gynecol 2011;37(1):27–33 Senat MV, Deprest J, Boulvain M, Paupe A, Winer N, Ville Y. Endoscopic laser surgery versus serial amnioreduction for severe twin-to-twin transfusion syndrome. N Engl J Med 2004;351(2): 136–144 Barrea C, Hornberger LK, Alkazaleh F, et al. 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 2006;195(5):1388–1395 Crombleholme TM, Shera D, Lee H, et al. A prospective, randomized, multicenter trial of amnioreduction vs selective fetoscopic laser photocoagulation for the treatment of severe twin-twin transfusion syndrome. Am J Obstet Gynecol 2007;197(4):e1–e9 Shah AD, Border WL, Crombleholme TM, Michelfelder EC. Initial fetal cardiovascular profile score predicts recipient twin outcome in twin-twin transfusion syndrome. J Am Soc Echocardiogr 2008; 21(10):1105–1108 Naeye RL. Organ abnormalities in a human parabiotic syndrome. Am J Pathol 1965;46(5):829–842 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(1):74–79 Quintero RA, Morales WJ, Allen MH, Bornick PW, Johnson PK, Kruger M. Staging of twin-twin transfusion syndrome. J Perinatol 1999;19(8 Pt 1):550–555 Habli M, Michelfelder E, Cnota J, et al. Prevalence and progression of recipient-twin cardiomyopathy in early-stage twin-twin transfusion syndrome. Ultrasound Obstet Gynecol 2012;39(1):63–68 O’Donoghue K, Cartwright E, Galea P, Fisk NM. Stage I twin-twin transfusion syndrome: rates of progression and regression in relation to outcome. Ultrasound Obstet Gynecol 2007;30(7): 958–964 Rossi AC, D’Addario V. Survival outcomes of twin-twin transfusion syndrome stage I: a systematic review of literature. Am J Perinatol 2013;30(1):5–10 Raboisson MJ, Fouron JC, Lamoureux J, et al. Early intertwin differences in myocardial performance during the twin-to-twin transfusion syndrome. Circulation 2004;110(19):3043–3048 Michelfelder E, Gottliebson W, Border W, et al. Early manifestations and spectrum of recipient twin cardiomyopathy in twintwin transfusion syndrome: relation to Quintero stage. Ultrasound Obstet Gynecol 2007;30(7):965–971 Moon-Grady AJ, Rand L, Gallardo S, Gosnell K, Lee H, Feldstein VA. Diastolic cardiac pathology and clinical twin-twin transfusion syndrome in monochorionic/diamniotic twins. Am J Obstet Gynecol 2011;205(3):279.e1–279.e11 Hofstaetter C, Hansmann M, Eik-Nes SH, Huhta JC, Luther SL. A cardiovascular profile score in the surveillance of fetal hydrops. J Matern Fetal Neonatal Med 2006;19(7):407–413 Stirnemann JJ, Mougeot M, Proulx F, et al. Profiling fetal cardiac function in twin-twin transfusion syndrome. Ultrasound Obstet Gynecol 2010;35(1):19–27 Rychik J, Tian Z, Bebbington M, et al. The twin-twin transfusion syndrome: spectrum of cardiovascular abnormality and development of a cardiovascular score to assess severity of disease. Am J Obstet Gynecol 2007;197(4):392.e1–e8 Stirnemann JJ, Nasr B, Proulx F, Essaoui M, Ville Y. 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. Ultrasound Obstet Gynecol 2010;36(1):52–57 Van Mieghem T, Martin AM, Weber R, et al. Fetal cardiac function in recipient twins undergoing fetoscopic laser ablation of placental anastomoses for Stage IV twin-twin transfusion syndrome. Ultrasound Obstet Gynecol 2013;42(1):64–69
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Fetal Echocardiography in Twin–Twin Transfusion Syndrome
Fetal Echocardiography in Twin–Twin Transfusion Syndrome 29 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(9210): 1157–1158 30 Berg C, Kremer C, Geipel A, Kohl T, Germer U, Gembruch U. Ductus venosus blood flow alterations in fetuses with obstructive lesions of the right heart. Ultrasound Obstet Gynecol 2006;28(2): 137–142 31 Rychik J, Zeng S, Bebbington M, et al. Speckle tracking-derived myocardial tissue deformation imaging in twin-twin transfusion syndrome: differences in strain and strain rate between donor and recipient twins. Fetal Diagn Ther 2012;32(1-2):131–137 32 Van Mieghem T, Giusca S, DeKoninck P, et al. Prospective assessment of fetal cardiac function with speckle tracking in healthy
Moon-Grady fetuses and recipient fetuses of twin-to-twin transfusion syndrome. J Am Soc Echocardiogr 2010;23(3):301–308 33 Zhao S, Deng YB, Chen XL, Liu R. Assessment of right ventricular function in recipient twin of twin to twin transfusion syndrome with speckle tracking echocardiography. Ultrasound Med Biol 2012;38(9):1502–1507 34 Crispi F, Sepulveda-Swatson E, Cruz-Lemini M, et al. Feasibility and reproducibility of a standard protocol for 2D speckle tracking and tissue Doppler-based strain and strain rate analysis of the fetal heart. Fetal Diagn Ther 2012;32(1-2):96–108 35 Taylor-Clarke MC, Matsui H, Roughton M, Wimalasundera RC, Gardiner HM. Ventricular strain changes in monochorionic twins with and without twin-to-twin transfusion syndrome. Am J Obstet Gynecol 2013;208(6):e1–e6
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Fetal Echocardiography in Twin–Twin Transfusion Syndrome Anita J. Moon-Grady, MD, FAAP, FACC, FASE1 1 Division of Cardiology, Department of Pediatrics and Fetal Treatment
Center, University of California San Francisco Benioff Children’s Hospital, San Francisco, California
Address for correspondence Anita J. Moon-Grady, MD, FAAP, FACC, FASE, Fetal Cardiovascular Program, 505 Parnassus Ave Box 0214, San Francisco, CA 94143 (e-mail: [email protected]).
Abstract
Keywords
► fetal echocardiography ► cardiomyopathy ► myocardial mechanics
Twin–twin transfusion syndrome is a complex disease process affecting monochorionic twin pregnancies that has implications for the cardiovascular system in both recipient and donor cotwins. Systolic, diastolic, and structural cardiac changes can occur; these have been the subject of intense study over the past two decades, and the use of echocardiography in evaluation of these pregnancies has become common in centers offering treatment of the condition. The role of echocardiography, the clinical cardiovascular and hemodynamic findings characteristic of the syndrome, and proposed pathophysiologic mechanisms and consequences are discussed in this review. Emerging technologies will be presented along with proposed areas for future research.
Twin–twin transfusion syndrome (TTTS) is a complication affecting monochorionic, diamniotic (MCDA) pregnancies at a rate of approximately 10 to 15%. The clinical diagnosis of TTTS is made sonographically by the presence of concurrent polyhydramnios (maximum vertical pocket 8 cm) in the recipient and oligohydramnios (2 cm) in the donor twin. Also seen to varying degrees are cardiac/hemodynamic changes in the recipient twin; donor twins, though less well studied, do not appear to exhibit deleterious functional abnormalities in utero in any of the studies published to date. The pathophysiology of the syndrome and of the development of cardiac involvement in the recipient remains incompletely understood. It has been postulated that abnormal or imbalanced vascular connections in the shared placenta may lead to chronic hypovolemia in the donor and volume overload in the recipient, which in combination with exposure to abnormal vasoactive mediators results in cardiac hypertrophy and cardiomegaly,1–4 with cardiac dysfunction (and ultimately hydrops). These cardiac changes are distinctly different, however, from those induced solely by volume overload or high-output states that lead to heart failure and hydrops, such as those seen in twin-reversed arterial perfusion or sacro-
coccygeal teratoma, in which cardiomegaly without hypertrophy precedes development of hydrops.5 Moreover, though all monochorionic twins including those with TTTS are at baseline at increased risk for congenital heart lesions including septal defects and more complex lesions,6,7 development of acquired structural heart disease can be seen in association specifically with TTTS, including pulmonary valve obstruction and mitral and tricuspid valve lesions.8–10 Treatment of TTTS with selective fetoscopic laser photocoagulation or serial amnioreduction has dramatically improved survival and outcomes in affected pregnancies,2,11 and laser treatment has been shown to significantly improve cardiovascular pathology seen antenatally in the recipient fetus.10,12 In this review, the types of cardiac changes that occur, proposed mechanisms, and methods for detection via echocardiography will be discussed. Ways in which the echocardiographic evaluation can complement the sonographic and the clinical evaluation and management of these pregnancies will be discussed; the role of echocardiography in short- and long-term prognostication and follow-up will be reviewed. Finally, newer methods and emerging technologies with their potential application to evaluation of this intriguing, evolving
received April 6, 2014 accepted April 18, 2014 published online June 10, 2014
Copyright © 2014 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662.
DOI http://dx.doi.org/ 10.1055/s-0034-1378146. ISSN 0735-1631.
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Am J Perinatol 2014;31:S31–S38.
Fetal Echocardiography in Twin–Twin Transfusion Syndrome disease process will be presented along with proposed areas for future research.
Pathophysiologic Considerations in the TTTS “Cardiomyopathy” In 2007, investigators participating in National Institute of Child Health and Human Development (NICHD)–funded North American trial of selective laser photocoagulation of placental anastomoses versus management with amnioreduction alone published a report of their findings.13 Although this trial, which was stopped before the planned sample size had been enrolled, was inconclusive with regard to superiority of laser therapy, subgroup analysis revealed a trend toward worse outcomes in recipient fetuses with preoperative cardiomyopathic changes including tricuspid and mitral regurgitation. The authors concluded that TTTS “cardiomyopathy” appeared to be an important determinant of survival in recipient twins. These findings were similar to those reported in a nonrandomized sample from a single institution.14 Interestingly, the pathophysiology of TTTS cardiomyopathy is less well understood than are the consequences for the fetus. Hypertrophy and hyperplasia, with increased heart weight, are common, even at earlier stages of disease15; tricuspid and mitral regurgitation and declining systolic function are seen particularly in the more advanced stages but are not universal. Several groups have shown that biomarkers associated with “heart failure” are elevated in the amniotic fluid of the recipient, including b-type natriuretic peptide4 as are certain vasoactive mediators including endothelin-1, and there is evidence for abnormal activation of the renin–angiotensin system.1,3 Exposure to these mediators, which result in increased afterload in the recipient, in combination with altered preload, may be the key feature in producing the systolic and diastolic cardiac pathology detected by echocardiography in fetuses at all stages of the disease. Less well understood is the acquisition of fibrotic and proliferative changes that affect the valves, particularly the pulmonary valve, and the endomyocardium of some of these fetuses.16
Role of Echocardiography in Prediction of Development/Progression of TTTS The most widely accepted means of describing the sonographic findings in established TTTS is the Quintero staging system.17 In stage I disease, only polyhydramnios and oligohydramnios are seen; in stage II, with worsened oliguria in the donor, the bladder is no longer seen; in stage III, Doppler abnormalities in the donor umbilical artery and/or the recipient ductus venosus are typically seen; and in stage IV hydropic changes are noted in one twin. The system is meant to be descriptive, and unfortunately pregnancies do not progress through stages in a predictable manner. Furthermore, since TTTS affects a minority of at-risk pregnancies, a tool capable of predicting the development of the condition would be quite useful and could potentially decrease the amount of screening done for unaffected pregnancies. American Journal of Perinatology
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Moon-Grady The twin pairs are usually normal in first trimester but may start to develop discordant fluid in the early second trimester; however, many of those pregnancies that develop discordant fetal size or fluid will not progress to true TTTS, or if they do develop Quintero stage I disease, up to 70 to 85% will not progress further.18–20 Once disease is stage II, nearly half can be expected to worsen, and at stages III and IV progression to severe disease resulting in the demise of one or both twins is almost universal—untreated, overall survival of advanced disease presenting < 26 weeks is only approximately 10 to 20%. Ideally, then, we would be able detect the MC gestation at risk for the development of TTTS that would require more intensive monitoring. In addition, we would want to have a reliable tool for the prediction of stable disease that might be managed expectantly versus disease at risk of progression. The issues surrounding progression of disease from stage I are complex and have been addressed in many forums. Until the results of a current trial randomizing patients with stage I disease to invasive therapy versus expectant management are available, there will be some debate how to optimally manage these pregnancies. Rossi and D’Addario20 published a systematic review of the literature as related to treatment modality for patients presenting with stage I TTTS. The authors found that laser therapy did not confer a survival advantage over conservative management overall, but also that when laser therapy was used as a primary therapy versus a secondary therapy after progression (while undergoing observation), it also did not prove advantageous. Survival was the same whether laser was first-line or “rescue” therapy. Given the apparent limitations of ultrasound staging in predicting disease progression, echocardiography may be an ideal tool for providing more detailed information about the cardiac status of the recipient fetus in pre-TTTS and early-stage TTTS pregnancies.
Echocardiography in Differentiating TTTS from Other Causes of Discordance in MCDA Twins In an early report looking at intertwin differences in timing intervals, as determined by pulsed-wave Doppler interrogation of ventricular inflow and outflow, known to lengthen with varying degrees of systolic (isovolumic contraction time) and diastolic (isovolumic relaxation time [IVRT]) cardiac dysfunction, Raboisson et al21 evaluated 23 TTTS cases and 11 twin pairs with selective intrauterine growth restriction in one twin. They reported an intertwin difference in both right and left ventricular IVRTs only in the pairs affected by TTTS. Several years later, Michelfelder et al22 reported that the right ventricular myocardial performance index or “MPI”(►Fig. 1) —a global measure of cardiac dysfunction encompassing alterations in both systole and diastole—was increased above normal in the majority of recipient twins across all Quintero stages of disease. Therefore, though apparently specific and somewhat sensitive for detection of the myopathic change in TTTS, these measures do not seem sensitive or specific enough for the detection of early disease. Recently, it has been shown that using a combination of tricuspid inflow duration (shortened in diastolic dysfunction and elevated afterload, ►Fig. 2) with IVRT and additional venous Doppler
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Fig. 1 Schematic to show measurement of isovolumic time intervals and calculation of MPI. The tracing is obtained using spectral Doppler, with atrioventricular (tricuspid or mitral) valve inflow in this example shown above and ventricular outflow below. IVCT, isovolumic contraction time; IVRT, isovolumic relaxation time; MPI, myocardial performance index.
parameters for detection of elevation in right atrial pressure (ductus venosus and systemic venous “a” wave velocity, ►Fig. 2), a pattern of early changes can be identified, which is present in recipient fetuses with stages I and II disease and that distinguishes them from twin pairs who do not have or develop disease. These patterns were also present in all of the fetuses in this series who progressed during observation, including those who did not have TTTS at the initial evaluation.23 This single-center experience supported earlier work and suggested that pregnancies at risk for developing TTTS should be evaluated by echocardiography. Further, it suggested that echocardiography may define a “prestage I” in MCDA pregnancies with discordant growth or discordant fluid before the detection of the polyhydramnios/ oligohydramnios that defines TTTS.
Echocardiography in Further Stratifying TTTS at Different Quintero Stages and in Prediction of Outcome The concept of development of a “profile” of cardiac findings that might help differentiate fetuses with TTTS of differing severity and prognosis has been extensively investigated. One method used is the cardiovascular profile score (CVPS) first proposed by Hofstaetter et al.24 The CVPS incorporates evaluation of fetal cardiac systolic function, cardiomegaly, the presence or absence of venous or arterial Doppler abnormalities, and the presence or absence of hydropic changes, generating a composite score of 0 to 10. Shah et al14 adapted the CVPS to TTTS pregnancies and reported on 62 twin gestations, finding that recipient twin survival was greater (50%) for those with a CVPS of 9 and 74% for a CVPS of 10. Furthermore, they found that among the components of the CVPS, atrioventricular valve regurgitation was associated with adverse recipient outcome.
Moon-Grady
Recently, Stirneman et al25 reported 63 cases evaluated before laser with complete echocardiographic data, and applied a multivariate description of the recipient’s cardiac function. Fifty-five percent of the stage I recipients had abnormal cardiac profiles at preoperative assessment in this series. Three different preoperative cardiac profiles were identified consisting of increasing right and left MPI, decreasing right and left shortening fraction, and increasing ductus venosus pulsatility index. The three retrospective group assignments represented progressive stages of TTTSrelated cardiomyopathy, though disappointingly no correlation was found with pregnancy outcome. The group from Cincinnati recently reported the results of a retrospective analysis of 123 pregnancies staged by Quintero staging and by the “Cincinnati Staging”8 algorithm, which incorporates echocardiographic variables previously discussed (►Table 1).18 The study group comprised 77 stage I and 46 stage II pregnancies. Overall the investigators saw a 56% rate of progression among Quintero stages I and II patients (two-thirds were stage I), with increasing relative risk of disease progression in higher Cincinnati stages (50% of Cincinnati stage IIIA, 100% of IIIB, and 67% of IIIC vs. only 40% of stages I and II that were not “upstaged” for cardiac changes) (►Fig. 3). The program at The Children’s Hospital of Philadelphia (CHOP) has published a method for systematically assessing echocardiographic data in TTTS pregnancies.26 The so-called “CHOP score” incorporates both donor (umbilical artery Doppler) and recipient assessments; the score is weighted toward recipient findings, with evaluation for the presence of cardiac hypertrophy, dilation, impaired systolic or diastolic function, atrioventricular valve regurgitation, pulmonary valve structural or Doppler abnormalities, and venous Doppler abnormalities. A composite score of 0 to 20 is generated, with “0” representing the best possible score and “20” being severely affected (►Table 2). Though initially reported as a descriptive score, attempts have been made to apply the CHOP score to prognostication, with disappointing results. Specifically, Stirnemann et al applied the CHOP score retrospectively to 158 pregnancies, all with TTTS27; survival of at least one twin occurred in 85, 95, 84, and 100% of Quintero stages I, II, III, and IV cases, respectively. In this report, CHOP scoring correlated with Quintero stage, but not with survival. Unfortunately, there were only a few fetuses in the worst categories (CHOP score > 10) in this series, limiting the conclusions that can be drawn about stratification using the CHOP score in fetuses with moderate to severe compromise. In summary, the “take-home” at present regarding echocardiographic assessment at presentation and “profiling” in TTTS is disappointing. Although it is still unclear that isolated polyhydramnios/oligohydramnios (stage I) needs treatment, these pregnancies should be monitored for progression with both echo and ultrasound. Echo parameters can be abnormal at all “stages” of TTTS even before diagnosis. These pregnancies should probably be even more closely monitored as echo abnormalities (moderate þ recipient cardiomyopathy) are predictive of progression from Quintero stage I to higher American Journal of Perinatology
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Fetal Echocardiography in Twin–Twin Transfusion Syndrome
Fetal Echocardiography in Twin–Twin Transfusion Syndrome
Moon-Grady
Fig. 2 Doppler indices of ventricular diastolic function evaluated in suspected twin–twin transfusion syndrome. The different Doppler parameters that were used to evaluate diastolic function in the recipient twin are illustrated. Doppler abnormality is defined as the presence of any one of the following: markedly fused or monophasic tricuspid inflow Doppler (upper panels), ductus venosus Doppler pattern S:a ratio > 3:1 (middle left panel), inferior vena cava flow reversal velocity-time integral (VTI) greater than 20% of forward flow velocity time integral (middle right panel), or abnormal umbilical venous flow (lower left panel). In addition, left ventricular isovolumic relaxation time is measured as shown (lower right panel) and compared with normal ranges established on an individual center basis. (Adapted with permission from Moon-Grady et al23.)
stages but not sensitive enough to predict progression in all pregnancies. Current profiling schemes are not useful for predicting pregnancy outcome after laser therapy or for prognosticating at higher (III, IV) Quintero stages. Clearly more study and experience is needed in this area.
Evolution of Cardiomyopathy and Acquired Valvar Dysplasias in TTTS There is an abundance of evidence that the appearance of the recipient cardiomyopathy largely resolves with delivery or
Table 1 Cincinnati staging scheme for twin–twin transfusion syndrome Stage
I
II
IIIA
IIIB
IIIC
III
IV
V
Donor
Oligo
þBladder not seen
Oligo
Oligo
Oligo
þAbnormal UA Doppler
Hydrops in one cotwin
Death of one cotwin
Recipient
Poly
Poly
Poly
Poly
Poly
þAbnormal DV Doppler
Hydrops in one cotwin
Death of one cotwin
None
None
Mild
Moderate
Severe
n/a
n/a
n/a
None
None
2–3 Z-score
3–4 Z-score
> 4 Z-score
n/a
n/a
n/a
None
None
2–3 Z-score
3–4 Z-score
Severe biventricular dysfunction
n/a
n/a
n/a
AVV regurgitation Ventricular hypertrophy MPI
Abbreviations: AVV, atrioventricular (tricuspid and/or mitral) valve; DV, ductus venosus; MPI, myocardial performance index; n/a, not applicable; Oligo, oligohydramnios (deepest vertical pocket /¼ 8 cm); UA, umbilical artery. Source: Adapted with permission from Habli et al.8 American Journal of Perinatology
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Fig. 3 Progression among twin–twin transfusion syndrome patients (Quintero stages I and II) as a function of recipient cardiomyopathy at presentation. Cincinnati stage IIIA, mild cardiomyopathy; Cincinnati stage IIIB, moderate cardiomyopathy; Cincinnati stage IIIC, severe cardiomyopathy. White denotes progression, gray no progression. (Reprinted with permission from Habli et al. 18)
laser therapy, and does so within weeks to months.10,12,28 Less well studied, however, are the potentially more permanent abnormalities of diastolic function and arterial distensibility that have been reported and have been proposed along the lines of the “Barker hypothesis” to be potential fetal origins of adult disease in these patients. Indeed, as early as the 1960s, Naeye reported histologic evidence of abnormal systemic arterial development in affected twins.15 In a single study evaluating arterial distensibility in infant (median age, 9 months) TTTS donor survivors, Cheung et al reported persistent abnormalities of arterial distensibility29 versus control twins. Affecting a minority of recipient twins, but with more clear postnatal consequences, are acquired valvar dysplasias. Most often seen and therefore most well described are right ventricular outflow tract obstructive lesions, valvar pulmonary stenosis, and atresia. Affecting approximately 11% of recipient twins in the prelaser era,16 laser therapy appears to decrease the incidence without totally eliminating it,10 suggesting that the valvar thickening and fibrosis seen histologically may be reversible in some fetuses. Interestingly, in singleton fetuses with pulmonary outflow obstruction, it is known that the ductus venosus “a” wave reversal is seen in up to 45% of mid-gestation fetuses without other evidence of compromise.30 Therefore, a careful assessment by echocardiography is necessary when ductus venosus “a” wave reversal is present, given it will heavily weight Quintero staging toward more “severe” (stage III þ ) disease when fetal compromise may or may not actually be present.
Moon-Grady
Less well described are acquired lesions of the tricuspid and mitral valves. In 2010, Losada et al9 reported for the first time an acquired structural abnormality of the mitral valve (“mitral arcade”) resulting in moderate to severe mitral regurgitation in the recipient twin and suggested that in stage III or IV disease, this finding may portend a particularly poor outcome. Given that 11 to 13% of TTTS recipients may have mitral regurgitation on echocardiogram,13,26 it is possible that evaluation for mitral disease may allow further stratification of these higher Quintero stage pregnancies. Indeed, what little data we have from the NICHD trial13 suggests, on post hoc analysis, that atrioventricular valve regurgitation may be an independent predictor of death. The hemodynamic implication of this finding proposes an interesting discussion. In the fetus with compromised right ventricular output, the left ventricle must compensate. What, then, is the effect of mitral regurgitation, compromised left ventricular filling, or myocardial fibrosis/cardiomyopathy on the ability of that ventricle to provide adequate output and oxygen delivery to the developing fetus? The effect of acquired mitral valve dysplasia in the setting of TTTS is an intriguing question that still has not been answered. Whether this acquired valvar dysplasia, like the pulmonary valve changes, can regress with laser therapy or delivery of the fetus is currently unknown. In summary, with respect to acquired heart disease in TTTS, hypertrophy and diastolic dysfunction in the recipient twin may be the tip of the iceberg in a systemic disease that affects both cotwins. In obstetric evaluation, standard (umbilical artery, ductus venosus) Doppler parameters need to be interpreted carefully and in the context of cardiac pathology especially right ventricular outflow tract obstruction. It has been demonstrated that very poor cardiac status leads to worse outcomes even with adequate therapy. There may be a plausible mechanism to explain this observation if left heart abnormalities accompany right-sided obstruction and/or failure. Echocardiography evaluation both before and after therapy will lead to better risk assessment not only for death but also for short- and long-term cardiac morbidity especially in the subset of patients with more severe/advanced disease at presentation.
Emerging Technologies Maturational and structural differences give rise to observed differences in cardiac function between fetal and postnatal life. Traditional M-mode, grayscale two-dimensional, and Doppler blood flow techniques discussed in this article give indirect insight into myocardial function and its interaction with the vasculature. Recently, several new indices derived from echocardiographic Doppler and tissue Doppler measurements have been proposed as noninvasive measures of systolic and diastolic dysfunction. Measurement of myocardial strain and strain rate using algorithms to track individual regional myocardial mechanics has been applied to several postnatal/adult disease states and to normal fetuses in a handful of recent publications. In the recipient twin in TTTS where there is evolution of ventricular hypertrophy, diastolic American Journal of Perinatology
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Fetal Echocardiography in Twin–Twin Transfusion Syndrome
Fetal Echocardiography in Twin–Twin Transfusion Syndrome
Moon-Grady
Table 2 Cardiovascular parameters used in The Children’s Hospital of Philadelphia scoring scheme Echocardiographic parameter
Score assigned
2D ventricular assessment Cardiomegalya Systolic dysfunction Hypertrophy
b
c
None (0)
Mild (1)
> Mild (2)
None (0)
Mild (1)
> Mild (2)
None (0)
Present (1)
Color Doppler AV valve assessmentd Tricuspid regurgitation
None (0)
Mild (1)
> Mild (2)
Mitral regurgitation
None (0)
Mild (1)
> Mild (2)
2 peaks (normal) (0)
Monophasic/fused (1)
2 peaks (normal) (0)
Monophasic/fused (1)
Spectral (PW) Doppler Tricuspid inflow Mitral inflow Ductus venosus “a” wave
e
Umbilical venous pulsations
All forward (0)
Decreased (1)
None (0)
Present (1)
Reversed (2)
Great vessel assessment 2D outflow tractsf
PA > Ao (0)
PA ¼ Ao (1)
PA < Ao (2)
Color Doppler
Forward flow, no pulmonary regurgitation (0)
Forward flow, pulmonary regurgitation seen (1)
RV outflow tract obstruction, revered ductal flow (3)
Normal (0)
“Decreased” diastolic flow (1)
Absent or reversed diastolic flow (2)
Donor assessment Umbilical artery Doppler
Abbreviations: Ao, aorta; AV, atrioventricular; PA, pulmonary artery; PW, pulsed-wave; RV, right ventricular; 2D, two-dimensional. Source: Adapted with permission from Rychik et al.26 a Cardiac size determined by cardiothoracic ratio by area method: Normal < 0.33, mild cardiomegaly 0.33–0.5, > mild cardiomegaly > 0.5. b Systolic dysfunction is assessed via qualitative assessment of ventricular function or shortening fraction with mild dysfunction 25–30%, > mild dysfunction < 25%. c Ventricular hypertrophy is assessed as present or absent based on qualitative assessment or right ventricular free wall > þ 2 Z-score for gestational age. d Atrioventricular valvar regurgitation is graded via color Doppler imaging of ratio of regurgitant jet area-to-atrial area; < 25% ¼ mild, > 25% ¼ > mild regurgitation. e Ductus venosus flow: atrial contraction velocity < 1/3 peak systolic velocity ¼ “mild” decrease. f Outflow tracts measurements are made at the semilunar valve annular level.
and eventual systolic dysfunction, right and left ventricular strain have been shown to be decreased.31–33 This is possibly related to alterations in afterload or due to myocardial hypertrophy, either of which may have the effect of decreasing tissue deformation. Rychik et al studied 25 pregnancies31 and demonstrated that recipient systolic strain rate and diastolic strain rate were significantly lower for both left and right ventricles in comparison to controls. The donor left ventricular systolic strain rate was higher and right ventricular diastolic strain rate was significantly lower than controls. In general, the feasibility of fetal strain measurement seems reasonable, though several studies report up to 20 to 30% interobserver variability and there are problems with application to individual fetuses and to disease states given the very wide confidence intervals reported in these studies.32,34 Taylor-Clarke et al have recently published data regarding an alteration of the technique to tighten the variability and have applied this methodology to TTTS with success.35 In a recent report comparing TTTS pregnancies with control unaffected twin pairs, they found that recipient American Journal of Perinatology
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left ventricular strain was reduced at all Quintero stages, while recipient right ventricular strain was reduced only in Quintero stages III and IV. Within-pair and between-ventricle values of strain in MCDA twin pairs without TTTS were similar. Left ventricular strain was reduced from early-stage TTTS in recipients but not donor cotwins. Strain improved at a median of 2 weeks following successful laser therapy. Study of TTTS using newer and more specific measures of myocardial mechanics stands to provide further insight into the pathophysiology of fetal myocardial disease and may help with prediction of prognosis as well as in guiding therapy. They may indeed contribute critically to the understanding of the evolution of normal and abnormal mechanics in the human heart and fetal cardiac adaptation to disease.
Summary and Recommendations TTTS produces an acquired cardiomyopathy in “recipient” twins in MC/DA pregnancies that is only partially understood but that can be identified and characterized using fetal echocardiography. The cardiomyopathy, as well as survival
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and neurologic outcomes, is improved with currently available laser therapy techniques. The optimal timing of intervention is yet to be determined and there may be a role for echocardiography in early detection/surveillance in the care of these patients. The role of echo in risk stratification is as yet unclear, but many advances have been made in the last decade. Postlaser and postnatal follow-up echocardiography and cardiac evaluation are recommended for both structural disease and long-term sequelae of cardiomyopathy and vasculopathy induced by the syndrome. Echo evaluation as part of routine ultrasound evaluation (early second trimester), and then as often as every 1 to 2 weeks during observation of affected pregnancies is warranted. When invasive therapy is performed, our current practice includes at a minimum follow-up cardiac evaluation at 24 hours, 1 week, and approximately 1 month after laser therapy. Consideration should be given to detailed postnatal cardiac evaluation in infancy for all survivors (donors and recipients) given the increased rates of both valvar dysplasias and what may initially be clinically silent disease as atrial septal defects, coarctation, patent ductus arteriosus are all increased in incidence in MCDA twins.7 Finally, coordinated efforts to further study known and emerging cardiac parameters in a systematic, multi-institutional collaborative setting is clearly needed to best determine the future role of echocardiography in the diagnosis and treatment of TTTS.
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