Fetal cardiovascular hemodynamics in twin twin transfusion syndrome

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1 AOGS REVIEW ARTICLE Fetal cardiovascular hemodynamics in twin twin transfusion syndrome CHRISTOPH WOHLMUTH 1,2, HELENA M. GARDINER 1, WERNER DIEHL 3 & KURT HECHER 3 1 The Fetal Center, UT Health School of Medicine, Houston, TX, USA, 2 Department of Obstetrics and Gynecology, Paracelsus Medical University, Salzburg, Austria, and 3 Department of Obstetrics and Fetal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany Key words Cardiovascular physiology, multifetal gestation, monochorionic twins, twin twin transfusion syndrome Correspondence Kurt Hecher, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, Hamburg, Germany k.hecher@uke.de Conflict of interest The authors have stated explicitly that there are no conflicts of interest in connection with this article. Please cite this article as: Wohlmuth C, Gardiner HM., Diehl W, Hecher K. Fetal cardiovascular hemodynamics in twin twin transfusion syndrome. Acta Obstet Gynecol Scand 2016; 95: Received: 3 October 2015 Accepted: 8 January 2016 DOI: /aogs Abstract Twin twin transfusion syndrome (TTTS) complicates 10 15% of monochorionic diamniotic (MCDA) pregnancies. It originates from unbalanced transfer of fluid and vasoactive mediators from one twin to its co-twin via placental anastomoses. This results in hypovolemia in the donor and hypervolemia and vasoconstriction in the recipient twin. Consequently, the recipient demonstrates cardiovascular alterations including atrioventricular valve regurgitation, diastolic dysfunction, and pulmonary stenosis/atresia that do not necessarily correlate with Quintero-stages. Selective fetoscopic laser photocoagulation of placental vascular anastomoses disrupts the underlying pathophysiology and usually improves cardiovascular function in the recipient with normalization of systolic and diastolic function within weeks after treatment. Postnatal studies have demonstrated early decreased arterial distensibility in ex-donor twins, but 10-year follow up is encouraging with survivors showing normal cardiovascular function after TTTS. However, prediction and appropriate early management of TTTS remain poor. Assessment of the cardiovascular system provides additional insight into the pathophysiology and severity of TTTS and may permit more targeted early surveillance of MCDA pregnancies in future. It should form an integral part of the diagnostic algorithm. Abbreviations: AA, arterioarterial; AV, arteriovenous; DCDA, dichorionicdiamniotic; DV, ductus venosus; MCDA, monochorionic diamniotic; MCMA, monochorionic monoamniotic; RAAS, renin angiotensin aldosterone system; SFLP, selective fetoscopic laser photocoagulation; TOPS, twin oligopolyhydramnios sequence; TTTS, twin twin transfusion syndrome; UA, umbilical artery; UV, umbilical vein; VV, venovenous. Introduction Monozygous ( identical or maternal ) twinning occurs in 1 in 330 spontaneous live births, when a fertilized egg splits into two separate individuals (1). Depending on the timing of the separation and the subsequent organization of the placenta and fetal membranes, four forms exist: (i) dichorionic diamniotic (DCDA, separate placenta and membranes, 25 30%), (ii) monochorionic diamniotic (MCDA, share one placenta, separate membranes, 70 75%), (iii) monochorionic monoamniotic (MCMA, share Key Message In twin twin transfusion syndrome, up to 70% of recipients show echocardiographic signs of anatomical or functional cardiac compromise. Diastolic dysfunction usually precedes and is more pronounced than systolic dysfunction. Donor fetuses typically have normal echocardiographic parameters at diagnosis. 664 ª 2016 Nordic Federation of Societies of Obstetrics and Gynecology, Acta Obstetricia et Gynecologica Scandinavica 95 (2016)

2 C. Wohlmuth et al. Cardiovascular hemodynamics in TTTS one placenta, fetuses lie within the same amniotic cavity, 1 2%) and rarely (iv) conjoined twins (0.25%) (1 4). The placental circulation as the origin of complications in MCDA pregnancies More than 95% of all monochorionic pregnancies have placental vascular anastomoses that connect the otherwise independent fetal circulations (5,6). These anastomoses can be arteriovenous (AV), arterioarterial (AA) or venovenous (VV). AA (Figure 1) and VV anastomoses are direct, superficial end-to-end anastomoses located on the chorionic plate and allow blood flow in both directions. AV anastomoses, on the other hand, are unidirectional and anastomose at a capillary level, where a cotyledon is supplied by an artery of one twin and blood is drained through a vein of the co-twin. The association between specific combinations of anastomoses and the development of complications in MCDA pregnancies and specifically twin twin transfusion syndrome (TTTS) has been studied extensively (5 9). Although there is no unique pattern, AV anastomoses are a prerequisite for, and are found in, 100% of TTTS placentas both in postnatal injection studies (5,6,9) and during fetoscopy (7). In contrast, AA anastomoses are rarer in TTTS placentas compared with uncomplicated MCDA pregnancies (10). TTTS develops when there is an imbalance of flow through these anastomoses with a net transfer of fluid across AV anastomoses from one twin to its co-twin that is not compensated for by AA or contralateral AV anastomoses. Yet, TTTS is not the result of simply a shift of blood from donor to recipient, rather, the twins are also exposed to the endocrine environment and vasoactive mediators produced by each other (11). TTTS pathophysiology The precise initiating mechanisms of TTTS remain uncertain; however, current understanding suggests that the Figure 1. Arterio-arterial anastomosis. Color and pulsed wave Doppler sonography of an arterio-arterial anastomosis with characteristic bidirectional pattern of blood flow. continuing volume shift results in hypervolemia in the recipient and hypovolemia in the donor. Natriuretic peptides are secreted from the recipient s cardiomyocytes in response to cardiac stretch, increasing glomerular filtration rate and decreasing tubular reabsorption, and so fostering polyuria and polyhydramnios (12 15). Hypoperfusion of the donor kidneys results in oliguria and oligohydramnios. This leads to an upregulation of renin secretion and activation of the renin angiotensin aldosterone system (RAAS) (16). Angiotensin II is a potent vasoconstrictor that increases peripheral vascular resistance and might initially be protective by maintaining the donor s blood pressure. Moreover, it causes secretion of aldosterone from the adrenal cortex, which increases tubular reabsorption of sodium and fluid to regulate against hypovolemia (16). Renin mrna is upregulated in donor kidneys and although downregulated in the recipient kidney (17,18), equally elevated cord blood renin levels have been observed in both twins (17,19,20). This supports the role of placental anastomoses in the transfer of RAAS components from donor to recipient. The chronic volume shift to the recipient fetus and the activation of RAAS in the donor aggravates renal hypoperfusion, resulting in persistent activation of RAAS and maintaining a vicious circle (16). Recipient cardiovascular pathophysiology Although no significant hemodynamic differences are usually found between uncomplicated MCDA twins (21), up to 70% of the recipients show echocardiographic signs of anatomical or functional cardiac compromise at the time of diagnosis, being confronted by both increased peripheral vascular resistance from vasoactive substances and volume-overload (22,23). Preload changes in the venous compartment demonstrate that umbilical venous (UV) flow is significantly higher in recipients than in donors (24). However, with advancing disease severity, UV flow decreases in recipients, indicating an increasingly impaired cardiac ability to accommodate venous return. The ductus venosus (DV) acts as a pressure transducer and reflects atrial filling pressure and afterload from ventricular end-diastolic pressure. Increased pressure is reflected in abnormal blood flow in the DV in advanced stages (25) showing increased pulsatility and subsequently absent or reversed flow during atrial contraction. With increasing distension of the venous compartment, the vascular compliance is reduced and pulsations can be transmitted into the UV (26). These mechanical events occur relatively late in the disease process, but DV time inter- ª 2016 Nordic Federation of Societies of Obstetrics and Gynecology, Acta Obstetricia et Gynecologica Scandinavica 95 (2016)

3 Cardiovascular hemodynamics in TTTS C. Wohlmuth et al. vals are altered in early-stage TTTS. Characteristically there is a relative prolongation of systolic flow and shortening of diastolic filling time, indicating poorer filling in the recipient heart (27,28). Diastolic dysfunction usually precedes and is more pronounced than systolic dysfunction. As such, monophasic ventricular filling (fusion of E and A wave) is observed in 20 30%, often with a measurable shortening of the ventricular filling time because of increased ventricular pressure. This combination results in important atrioventricular valve regurgitation often extending throughout more than half of the cardiac cycle (25,29,30). It also causes a prolongation of the isovolumic relaxation time, thus increasing the myocardial performance (Tei) index (Figure 2a,b). This is a measurement of global cardiac function; it is load dependent and does not measure myocardial velocities (31 33). The latter can be quantified by speckle-tracking, a non-doppler technique tracking the endocardial border. It allows quantification of velocity, displacement, strain, and strain rate and is therefore a better measure of myocardial function. Ventricular strain of both ventricles is decreased in recipients already in the early stages of TTTS reflecting the early changes in afterload (34,35). The elevated levels of circulating vasomediators such as angiotensin II and endothelin I result in recipient myocardial hypertrophy (36) and fetal hypertension, inferred by tricuspid regurgitant velocities (37). Hypertension was also confirmed by others after birth in the era when serial amnioreduction was the only therapeutic option (38). Absent or reversed end-diastolic flow in the umbilical artery (UA) is a less common finding in the recipient and may reflect placental compression from polyhydramnios or true heart failure where systolic function is severely reduced (25). Anatomical pulmonary stenosis/atresia is over-represented in MCDA twins and reported in the absence of TTTS (21). In contrast, functional pulmonary stenosis/ atresia is the result of severe right heart dysfunction and resolves completely following laser therapy in most cases (36) (Figure 3). Donor cardiovascular pathophysiology Donor fetuses usually show normal echocardiographic parameters at diagnosis (39). Around 3 10% present with abnormal Doppler waveforms or UV pulsations (25,33). Due to hypovolemia the DV inlet dilates and allows more shunting of blood through the DV. This promotes an increased transmission of the pulse wave into the UV (26). Absence or reversal of end-diastolic velocities in the UA may be due to a primary maldevelopment of the placenta and unequal placental sharing combined with hemodynamic imbalance and hypovolemia (25). Figure 2. (a) Myocardial performance (Tei) index pulsed wave Doppler. The pulsed wave Doppler sample is placed in the left ventricle, simultaneously acquiring MV inflow and LVOT. MPI is calculated from the sum of isovolumic contraction time and isovolumic relaxation time divided by ejection time. (b) Myocardial performance (Tei) index tissue Doppler. The tissue Doppler-derived MPI can be obtained for both ventricles. In a four-chamber view, the Doppler sample gate is placed at the left and right ventricular annulus kept at an angle of less than 30. Abbreviations: ET, ejection time; ICT, isovolumic contraction time; IRT, isovolumic relaxation time; LVOT, left ventricular outflow tract; MPI, myocardial performance index; MV, mitral valve; PW, pulsed wave. Diagnosis In 1999, Quintero et al. suggested a staging system based on a proposed sequence of pathophysiological events in TTTS, that correlated with postnatal outcome in a retrospective series (40). Subsequent studies did not confirm prediction of outcome by Quintero stages (41,42). Michelfeldner et al. reported cardiac dysfunction in up to half of recipient fetuses already in the early stages of TTTS (43). The Quintero staging system does not include abnormal cardiovascular physiology, other than Doppler changes in the UA, UV or DV (Figure 4). Subsequently, attempts have been undertaken to improve the current TTTS classification using cardiovascular parameters. The most extensive is the CHOP cardiovascular score for TTTS. It is partly overlapping with the Quintero staging and includes 11 items quantifying alterations in the recipient and only one the UA Doppler in the donor (29). Unfortunately, studies have failed to demonstrate a 666 ª 2016 Nordic Federation of Societies of Obstetrics and Gynecology, Acta Obstetricia et Gynecologica Scandinavica 95 (2016)

4 C. Wohlmuth et al. Cardiovascular hemodynamics in TTTS (a) (b) Figure 3. Functional pulmonary atresia before and after selective fetoscopic laser photocoagulation. (a) Functional pulmonary atresia with reverse flow in the pulmonary trunk in a recipient with advanced stage twin twin transfusion syndrome. (b) Reappearance of forward flow through the pulmonary trunk and arterial duct 24 h after successful selective fetoscopic laser photocoagulation. Abbreviations: AD, arterial duct; AO, aorta; PT, pulmonary trunk; RV, right ventricle. correlation of this score with outcome after laser therapy, which may be because the influences on outcome measures are multifactorial (23,44). We routinely perform anatomical and functional fetal echocardiography in TTTS fetuses. Our protocol at the Fetal Center in Houston includes (i) assessment of ventricular filling, (ii) valvar regurgitation, (iii) myocardial performance index, (iv) long-axis function and tissue Doppler imaging, (v) estimated biventricular cardiac output, (vi) semilunar valve peak velocities, and (vii) UA, UV, DV, and MCA waveforms. Since the report of improved recipient survival with nifedipine administration (45), we offer enrollment in a trial of nifedipine treatment in cases with significant cardiac involvement. In the study of Crombleholme et al., no adverse outcome was observed in the donor, but the effects of nifedipine on the fetal cardiovascular system warrant further study (45). To date, no tool is available to reliably predict the development of TTTS. From a pathophysiological perspective the cardiovascular system is likely affected early in the disease pathogenesis. Therefore, attempts have been undertaken to predict the development of TTTS. One study showed subtle changes in LV strain already in pre-ttts cases that did not fulfill the disease criteria, but went on to develop TTTS (34). Strain analysis therefore merits consideration as a potential early indicator of TTTS. Similarly, abnormal ductus venosus flow or discordant nuchal translucency in the first trimester have been reported (46 48). But these findings are neither very sensitive nor specific. Differential diagnosis Twin anemia polycythemia syndrome is a chronic form of TTTS that occurs at a slower rate and is characterized by only few and small unidirectional AV anastomoses (9). Figure 4. Fetal assessment according to Quintero staging is based on the presence of amniotic fluid discordance (Donor-MVP <2 cm, Recipient-MVP >8 cm*), absence of donor bladder filling, abnormal fetal Doppler and fetal hydrops in either twin and does not include abnormal cardiac function. *Most European countries use a gestational-age-specific cut-off for the definition of polyhydramnios in the recipient: GA <20 weeks: MVP >8 cm; GA >20 weeks: MVP >10 cm. Abbreviations: DV, ductus venosus; GA, gestational age; MVP, maximal vertical pocket; UA, umbilical artery; UV, umbilical vein. This results in large intertwin hemoglobin differences without twin oligopolyhydramnios sequence (TOPS) and likely without the resulting endocrine imbalance (49,50). Although it is not entirely clear why TOPS does not evolve, it is assumed that the slow rate of transfusion allows more time for hemodynamic compensatory mechanisms (8,51). Therefore the diagnosis is based on the presence of discordant middle cerebral artery peak systolic velocity measurements: donor >1.5 multiples of the median and recipient <1 multiples of the median (51). Selective intrauterine growth restriction is another important complication in MCDA pregnancies that occurs in about 10 15% (5,46). Again, unlike in TTTS, ª 2016 Nordic Federation of Societies of Obstetrics and Gynecology, Acta Obstetricia et Gynecologica Scandinavica 95 (2016)

5 Cardiovascular hemodynamics in TTTS C. Wohlmuth et al. there is no TOPS and unequal placental sharing seems to be the most important determinant of unequal growth (52,53). Hence, mainly the smaller twin is affected and the prognosis largely depends on the onset and severity of growth restriction as well as Doppler characteristics in the smaller twin (54,55). However, the tightly linked intertwin circulation may result in dual fetal demise, with type III selective intrauterine growth restriction being the most unpredictable form where large AA anastomoses are present (54,55). Antenatal therapy and its implication on the cardiovascular system The only specific treatment for TTTS is selective fetoscopic laser photocoagulation (SFLP) of placental vascular anastomoses. In 2004, the Eurofetus trial proved the superiority of laser treatment over serial amnioreduction in terms of survival and neurologic morbidity (56). It disrupts the underlying pathophysiology and results in rapid improvement of the cardiovascular function in the recipient with normalization of systolic and diastolic function (22,33,57). Both preload and afterload are altered by SFLP, demonstrated by a significant decrease in DV pulsatility index and normalization of time intervals with lengthening of filling times, reflecting improved diastolic heart function in the recipient (25,28). This is also shown in a significant improvement of left- and right-ventricular Tei index and an increase in the shortening fraction after SFLP (57). In advanced TTTS, SFLP can reverse pulmonary atresia (57). Figure 3 shows functional pulmonary atresia with reversal of flow in the arterial duct in a recipient twin that normalized within 24 h following successful SFLP. In the donor, reappearance of end-diastolic flow in the UA and a significant decrease of pulsatility index after the procedure are compatible with an increase in blood volume and blood pressure (25,58). Measurements suggest that the weight-corrected UV flow is increased by more than 50% in the vasoconstricted donor within 48 h of SFLP and the magnitude of increase correlates with reappearance of bladder filling reflecting improved renal perfusion. This relative volume-overload can result in a temporary increase in the donor DV Doppler pulsatility index and is occasionally accompanied by transient donor hydrops (25,33,58,59). Cardiovascular long-term implications Dual survival in TTTS was rare during the era of serial amnioreduction, before SFLP was established as the therapy of choice. The earlier reports on cardiovascular outcome reflect the effects of long duration disease, often weeks of TTTS before delivery, and potential adverse effects from co-twin demise. Myocardial hypertrophy, important tricuspid regurgitation, and pulmonary valve stenosis requiring postnatal balloon valvuloplasty were commonplace in the ex-recipient neonate in this era (36,38,60). Neonatal cardiovascular physiology is now improved, in part because disease duration is much shorter than in previous years and SFLP is performed several weeks before delivery, thus allowing time for cardiac remodeling and resolution of tricuspid regurgitation (61). Early reports suggested decreased arterial distensibility in the ex-donor infants treated by serial amnioreduction. However, 11-year follow up of four cohorts of twins treated with serial amnioreduction or SFLP and two control groups (MCDA, DCDA) reports no hypertension in the survivors of TTTS during prepubescence. The placental anastomoses allowing connection of the fetal circulations are associated with lower systolic and diastolic blood pressures in the MCDA cohort along with increased capillary blood flow compared with DCDA twins and MCDA treated with SFLP (62 64). Functional cardiac assessment does not show any significant differences between ex-donor and ex-recipient twin pairs treated by SFLP in the medium term outcome (65 69). However, pulmonary stenosis is over-represented in MCDA twins compared with the general population and is also seen without TTTS (21,69). This suggests a shared genetic etiology that requires further study. Conclusion TTTS is associated with significant morbidity and mortality if left untreated. Although the Quintero staging helps to classify disease severity and allows proper referrals, it does not aid prediction of the development of disease. Assessment of the cardiovascular system provides a more fundamental insight into the pathophysiology and severity of TTTS and should form an integral part of the management of MCDA pregnancies. Acknowledgment We would like to thank the Paracelsus Medical University Research Fund for the financial support of the fellowship of Dr Christoph Wohlmuth (PMU-FFF L-15/02/ 003- WOH). References 1. Hall JG. Developmental biology IV Twinning. Lancet. 2003;362: ª 2016 Nordic Federation of Societies of Obstetrics and Gynecology, Acta Obstetricia et Gynecologica Scandinavica 95 (2016)

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