echocardiography in Twins

CHAPTER I
INTRODUCTION
Twin to twin transfusion syndrome (TTTS) is a severe complication of monochorionic
twin pregnancies. It carries a high risk of fetal death if left untreated (80–100%) and a high
perinatal morbidity and mortality. In TTTS, genetically identical twins are exposed to
different haemodynamic conditions and environmental factors. Placental vascular
anastomoses provide the anatomical basis for the unbalanced intertwin transfusion from
donor to recipient. In the hypervolaemic recipient, cardiomegaly, biventricular hypertrophy,
and tricuspid and mitral regurgitation precede the development of more severe cardiac
dysfunction and may result in fetal hydrops as the end stage of intrauterine heart failure.
Cardiac dysfunction progresses with increasing gestational age. In addition, various types of
cardiac defects predominantly affecting the right ventricle and pulmonary artery have been
reported. These include muscular right ventricular outflow obstruction, valvar pulmonary
stenosis and atresia, and left ventricular hypertrophic non-obstructive and obstructive
cardiomyopathy. In contrast, the hypovolaemic donor twin shows little cardiac pathology on
fetal echocardiography but does manifest increased afterload due to raised placental
resistance, as well as evidence of poor renal perfusion.1
Both fetuses

are at risk of death and of short- and long-term cardiocirculatory

complications, which have been reported to decrease when early treatment is provided.
Unfortunately, early in the process, TTTS is difficult to differentiate from intrauterine growth
restriction (IUGR) due to placental circulatory insufficiency; at this stage, discordances in
fetal growth and amniotic fluid volumes are first signs shared by both conditions. During the
course of TTTS, hypertrophic cardiomyopathy is observed in the recipient twin; its
pathogenesis remains unclear. Pressure rather than volume overload is increasingly
considered as a key factor given the reports of elevated concentration of endothelin in the
recipient twin and upregulation of the renin-angiotensin system in the donor twin. If this were
the case, subclinical evidence of cardiac dysfunction could be among the first signs observed
with TTTS, whereas in IUGR, no difference in myocardial performance should be expected,
at least early in the process when impairment in fetal oxygenation is still well compensated. 2
Twin-twin transfusion syndrome (TTTS) occurs in 10% to 20% of monozygous twin
gestations and is an important cause of perinatal mortality in monochorionic twins with very
high mortality rates if untreated. The syndrome is characterized clinically by polyhydramnios
in 1 twin and oligohydramnios in the other. The pathophysiology of the syndrome is
1

incompletely understood; however, it has been speculated that an imbalance in net blood
supply to the recipient fetus resulting from abnormal placental vascular connections,
combined with exposure to circulating abnormal vasoactive mediators, produces the
syndrome. In the recipient twin, TTTS can lead to cardiovascular compromise, which can be
detected antenatally by ultrasound. On echocardiography, the most common abnormalities
seen in recipient twins are ventricular hypertrophy (18% to 49% of cases), increased
cardiothoracic ratio (as high as 47%), ventricular dilation (17% to 31%), tricuspid
regurgitation (35% to 52%), and mitral regurgitation (13% to 15%). In addition, cases of
acquired pulmonary stenosis/atresia in the recipient twin have been reported.3

2

CHAPTER II
TWIN-TO-TWIN TRANSFUSION SYNDROME5,7,8
Management of Twin-Twin Transfusion Syndrome (TTTS) is one of the most
challenging clinical problems concerning multiple gestations. Approximately 20 percent of
all twin pregnancies are monochorionic, and the incidence of TTTS in monochorionic
diamniotic gestations is approximately 5 to 15 percent. TTTS is a phenomenon almost
exclusive to monochorionic pregnancies.

The natural history of severe TTTS is well established with mortality rates approaching 80 to
100 percent if left untreated, especially when it presents prior to 20 weeks gestation in which
case it tends to be more severe and more rapidly progressive. This is particularly troublesome
given that two structurally normal fetuses are involved.
Twin-twin transfusion syndrome (TTTS) is diagnosed prenatally by ultrasound. The
Diagnosis requires 2 criteria: (1) the presence of amonochorionic diamniotic (MCDA)
pregnancy; and (2) the presence of oligohydramnios (defined as a maximal vertical pocket
[MVP] of <2cm) in one sac, and of polyhydramnios (a MVP of >8 cm) in the other sac
(Figure 1). MVP of 2 cm and 8 cm represent the 5th and 95th percentiles for amniotic fluid
measurements, respectively, and the presence of both is used to define stage I TTTS. If there
is a subjective difference in amniotic fluid in the 2 sacs that fails to meet these criteria, pro-

3

gression to TTTS occurs in <15% of cases. Although growth discordance (usually defined as
>20%) and intrauterine growth restriction (IUGR) (estimated fetal weight <10%for
gestational age) often complicate TTTS, growth discordance itself or IUGR itself are not
diagnostic criteria. The differential diagnosis may include selective IUGR, or possibly an
anomaly in 1 twin causing amniotic fluid abnormality.

Twin anemia-polycythemia sequence (TAPS) has been recently described inMCDA
gestations, and is defined as the presence of anemia in the donor and polycythemia in the
recipient, diagnosed antenatally by middle cerebral artery (MCA)–peak systolic velocity
(PSV) >1.5 multiples of median in the donor and MCA PSV <1.0 multiples of median in the
recipient, in the absence of oligohydramnios polyhydramnios.
The most commonly used TTTS staging systemwas developed byQuintero et al in
1999, and is based on sonographic findings. The TTTS Quintero staging system includes 5
stages, ranging from mild disease with isolated discordant amniotic fluid volume to severe
disease with demise of one or both twins (Table 1and Figures 2 and 3). This system has some
prognostic significance and provides a method to compare outcome data using different
therapeutic interventions. Although the stages do not correlate perfectly with perinatal
survival, it is relatively straightforward to apply,may improve communication between
patients and providers, and identifies the subset of cases most likely to benefit from treatment.
Since the development of the Quintero staging system, much has been learned about the
changes in fetal cardiovascular physiology that accompany disease progression (discussed
4

below). Myocardial performance abnormalities have been described, particularly in recipient
twins, including those with only stage I or II TTTS.

Approximately one-third of twins are monozygotic (MZ), and three-fourths of MZ
twins are MCDA. In general, only twin gestations with MCDA placentation are at significant
risk for TTTS, which complicates about 8-10% of MCDA pregnancies. TTTS is very
uncommon in MZ twins with dichorionic or monoamniotic placentation. Although most twins
conceived with in vitro fertilization (IVF) are dichorionic, it is important to remember that
there is a 2- to 12-fold increase in MZ twinning in embryos conceived with IVF, and
TTTS can therefore occur for IVF MCDA pregnancies.

5

In current practice, the prevalence of TTTS is approximately 1-3 per 10,000 births.
The presentation of TTTS is highly variable. Because pregnancieswith TTTS often receive
care at referral centers, data about the stage of TTTS at initial presentation (ie, to nonreferral
centers) are lacking in the literature. Fetal therapy centers report that about 11-15%of their
cases at referral were Quintero stage I (probably underestimated as some referral centers did
not report stage I TTTS cases), 20-40% were stage II, 38-60% were stage III, 6-7% were
stage IV, and 2%were stage V.
Although TTTS may develop at any time in gestation, the majority of cases are
diagnosed in the second trimester. Stage I may progress to a nonvisualized fetal bladder in the
donor (stage II) (Figure 2), and absent or reversed end-diastolic flow in the umbilical artery of
donor or recipient twins may subsequently develop (stage III) (Figure 3), followed by
hydrops (stage IV). However, TTTS often does not progress in a predictable manner. Natural
history data by stage are limited, especially for stages II-V, as staging was initially proposed
in 1999. This is because most natural history data were published before 1999, and
thereforewas not stratified by stage (Table 2).
Underlying Pathophysiology
The primary etiologic problem underlying TTTS is thought to lie within the
architecture of the placenta, as intertwin vascular connections within the placenta are critical
for the development of TTTS. Virtually allMCDA placentas have anastomoses that link the
circulations of the twins, yet not all MCDA twins develop TTTS. There are 3 main types of
anastomoses in monochorionic placentas: venovenous (VV), arterioarterial (AA), and
arteriovenous (AV). AV anastomoses are found in 90-95% of MCDA placentas, AA in 8590%, and VV in 15-20%.

6

Both AA and VV anastomoses are direct superficial connections on the surface of the
placenta with the potential for bidirectional flow (Figure 4). In AV anastomoses, while the
vessels themselves are on the surface of the placenta, the actual anastomotic connections
occur in a cotyledon, deep within the placenta (Figure 4).AVanastomoses can result in
unidirectional flow fromone twin to the other, and if uncompensated,may lead to an
imbalance of volume between the twins. Unlike AA and VV, which are direct vessel-to-vessel
connections, AV connections are linked through large capillary beds deepwithin the
cotyledon.
AV anastomoses are usually multiple and overall balanced in both directions so that
TTTS does not occur. While the number of AV anastomoses from donor to recipient may be
important, their size aswell as placental resistance likely influences the volume of intertwin
transfusion that occurs. Placentas in twins affected with TTTS are reportedly more likely to
have VV, but less likely to have AA anastomoses. It is thought that these bidirectional
anastomoses may compensate for the unidirectional flow through AV connections, thereby
preventing the development of TTTS or decreasing its severitywhen it does occur.
Mortality is highest in the absence of AA and lowest when these anastomoses are
present (42% vs 15%). However, the presence of AA is not completely protective, as about
25-30%of TTTS casesmay also have these anastomoses. The imbalance of blood flow
through the placental anastomoses leads to volume depletion in the donor twin, with oliguria
and oligohydramnios, and to volume overload in the recipient twin,with polyuria and
polyhydramnios. There also appear to be additional factors beyond placentalmorphology,
such as complex interactions of the renin-angiotensin systemin the twins, involved in the
development of this disorder.
7

Management
The management options described for TTTS include expectant management,
amnioreduction, intentional septostomy of the intervening membrane, fetoscopic laser
8

photocoagulation of placental anastomoses, and selective reduction. The interventions that
have been evaluated in randomized controlled trials (RCTs) include intentional septostomy of
the intervening membrane to equalize the fluid in both sacs, amnioreduction of the excess
fluid in the recipient’s sac, and laser abla tion of placental anastomoses. There have been 3
randomized trials designed to evaluate some of the different treatment modalities for TTTS,
all of which were terminated prior to recruitment of the planned subject number after interim analyses, as discussed below. Despite the limitations and early termination of these
clinical trials, they represent the best available data upon which to judge the various
treatments for TTTS Consultation with a maternal-fetal medicine specialist is recommended,
particularly if the patient is at a gestational age at which laser therapy is potentially an option.
In evaluating the data, considerations include the stage of TTTS, the details of the
intervention, and the perinatal outcome. The most important outcomes reported are overall
perinatal mortality, survival of at least 1 twin, and, if available, long-term outcomes of the
babies, including neurologic outcome. Extensive counseling should be provided to patients
with pregnancies complicated by TTTS, including natural history of the disease, as well as
management options and their risks and benefits.
Expectant management involves no intervention. This natural history of TTTS, also
called conservative management, has limited outcome data according to stage, particularly
for advanced disease (Table 2). It is important that the limitations in the available data are
discussed with the patient with TTTS, and compared with available outcome data for
interventions.
Amnioreduction involves the removal of amniotic fluid from the polyhydramniotic sac of the recipient. It is usually done only when theMVP is >8 cm, with an aim to
correct it to a MVP of <8 cm, often to <5cm or <6 cm. Usually an 18 or 20 gauge needle is
used. Some practitioners use aspiration with syringes, while some use vacuum containers.
Amnioreduction can be performed either as a 1-time procedure, as t times this can resolve
stage I or II TTTS, or serially, eg, every time theMVP s >8 cm. It can be performed any time
>14 weeks. Amnioreduction is hypothisized to reduce the intraamniotic and placental
intravascular pressures, potentially facilitating placental blood flow, and/or to possibly reduce
the incidence of preterm labor and birth related to polyhydramnios. Amnioreduction may
be used also >26 weeks, particularly in cases with maternal respiratory distress or preterm
contractions from polyhydramnios. Amnioreduction has been associated with average
survival rates of 50%, with large registries reporting 60-65% overall survival. However, serial
amnioreduction is often necessary, and repeated procedures increase the likelihood of
9

complications such as preterm premature rupture of themembranes, preterm labor, abruption,
infection, and fetal death. Another consideration is that any invasive procedure prior to
fetoscopy may decrease the feasibility and success of laser due to bleeding, chorioamnion
separation, inadvertent septostomy, or membrane rupture.
Septostomy involves intentionally puncturing with a needle the amniotic membranes
between the 2 MCDA sacs, theoretically allowing equilibration of amniotic fluid volume in
the 2 sacs. In the 1 randomized trial in which it was evaluated, the intertwin membrane was
purposefully perforated under ultrasound guidance with a single puncture using a 22-gauge
needle. This was usually introduced through the donor’s twin gestational sac into the
recipient twin’s amniotic cavity. If reaccumulation of amniotic fluid in the donor twin sac was
not seen in about 48 hours, a repeat septostomy was undertaken. Intentional septostomy is
mentioned only to note that it has generally been abandoned as a treatment for TTTS. It is
believed to offer no significant therapeutic advantage, and may lead to disruption of the
membrane and a functional monoamniotic situation. A randomized trial of amnioreduction vs
septostomy ended after an interimanalysis found that the rate of survival of at least 1 twin
was similar between the 2 groups, and that recruitment had been slower than anticipated. In
all, 97% of the enrolled pregnancies had stages I-III TTTS, and results were not otherwise
reported by stage. In 40% of the septostomy cases, additional procedures were needed. No
data on neurologic outcome are available.
Laser involves photocoagulating the vascular anastomoses crossing from one side of
the placenta to the other. This is usually performed by placing a sheath and passing an
endoscope under ultrasound guidance. Ultrasound is also used to map the vasculature to
determine the placental angioarchitecture. The primary theoretical advantage of laser
coagulation is that it is designed to interrupt the placental anastomoses that give rise to TTTS.
The goal of laser ablation is to functionally separate the placenta into 2 regions, each
supplying one of the twins. This unlinking of the circulations of the twins is often referred to
as “dichorionization” of the monochorionic placenta. Adequate visualization of the vascular
equator that separates the cotyledons of one twin from the other is critical for laser
photocoagulation. Selective coagulation of AV as well as AA and VV anastomoses is
preferred over nonselective ablation of all vessels crossing the separating membrane as it
appears to lead to fewer procedure-related fetal losses. Sequential coagulation of the donor
artery to recipient vein followed by recipient artery to donor vein may theoretically allow
some return of fluid fromthe recipient to the donor prior to severing other connections.
Criteria for laser have included MCDA pregnancies between about 15-26 weeks with the
10

recipient twin having MVP ≥8.0 cm at ≤20 weeks or ≥10.0cm at >20 weeks and a distended
fetal bladder, and donor twin having MVP ≤2.0 cm in 1 trial, and MCDA pregnancies at < 24
weeks with the recipient twin having MVP >8 cm, and donor twin having MVP ≤2cm and
nonvisualized fetal bladder in the other. There is insufficient evidence to recommend
management inMCDA pairs with TTTS in higher-order multiple gestations, but laser has
been proposed as feasible and effective.
Selective reduction involves purposefully interrupting umbilical cord blood flow of 1
twin, causing the death of this twin, with the purpose of improving the outcome of the other
surviving twin. Usually the cord occlusion is performed with radiofrequency ablation or cord
coagulation, but other procedures have been employed. Obviously this option can be
associated with a maximum of 50% overall survival, so, if ever considered, it is usually
reserved for stages III or IV TTTS only.

Antenatal Monitoring for Pregnancies Complicated by TTTS
There are no randomized trials to evaluate the effectiveness of antenatal monitoring
for pregnancies complicated by TTTS. Weekly monitoring of the umbilical artery Doppler
flow and MVP of amniotic fluid of each fetus may be considered. The evidence for
11

effectiveness of serial (eg, weekly or twice/wk) nonstress tests, biophysical profiles, and other
antenatal testing modalities is insufficient to make a recommendation, but these tests can be
considered. One reason for surveillance, even following laser therapy, is that not all
anastomoses are ablated at the time of laser. Residual anastomoses, either initially undetected,
missed, or revascularized after laser, have been observed in up to a third of cases. Placental
casting has also demonstrated the presence of deep, atypical AV anastomoses beneath the
chorionic plate thatwould not be visible by fetoscopy. Failure to coagulate all AV
anastomoses can lead to persistent, recurrent or reversed TTTS. Persistent or recurrent TTTS
has been reported in 14%of cases postlaser and reversed TTTS, with the recipient becoming
anemic and the donor polycythemic, in 13% of cases. While TAPS can occur spontaneously
in a MCDA gestation, it is a known iatrogenic complication of laser.
Screening by transvaginal ultrasound for short cervical length in TTTS cases has also
been proposed, as this is associated with preterm birth, a known complication of TTTS. As
there are no interventions shown to improve outcome based on short transvaginal ultrasound
cervical length in TTTS cases, this screening cannot be recommended at this time.

12

CHAPTER III
CARDIOMYOPATI IN TWIN-TO-TWIN TRANSFUSION SYNDROME4
Cardiovascular compromise occurs in most recipient twins, is a major cause of death
for these fetuses, and contributes to morbidity and mortality in the donor cotwin. As early as
1992, specific recipient echocardiographic abnormalities were reported. These abnormalities
are tricuspid regurgitation, ventricular hypertrophy, increased cardiothoracic ratio, and
pulmonary stenosis. An echocardiographic examination of the twins is thus an essential
component of the initial workup of TTTS. Then, during the antenatal and postnatal periods,
follow-up evaluation for progression of the disease is also necessary. The recipient twin
manifests a cardiomyopathy that is progressive in nature. At first, right ventricular dilatation
and hypertrophy can be identified to a greater degree than ventricular dilatation and
hypertrophy in the left ventricle. However, as the process progresses, right and left
ventricular hypertrophy become more pronounced. This hypertrophy is associated with
atrioventricular valve regurgitation involving first tricuspid regurgitation and then mitral
valve regurgitation. Estimates of right ventricular pressures based on flow velocity of
tricuspid regurgitation jet suggest that recipient cardiomyopathy is a hypertensive
cardiomyopathy. Right ventricular pressures in excess of 70 mm Hg are common. The cause
of this hypertensive cardiomyopathy is postulated to be due to vasoactive substances from the
placenta or donor twin. The recipient twin experiences an increase in blood volume,
vasoconstriction, and ventricular hypertrophy, possibly mediated by angiotensin II and
endothelin-1.
The most common recipient cardiovascular abnormalities in TTTS are unilateral or
bilateral ventricular hypertrophy (ranges 18%-49%), increased cardiothoracic ratio as high as
47%, ventricular dilation (ranges 17%-31%), tricuspid regurgitation (ranges 35%-52%), and
mitral regurgitation (ranges 13%-15%). These abnormalities are more common with
advanced stages of disease. Finally, several cases of acquired pulmonary atresia/stenosis with
intact ventricular septum have been described in the recipient twin.
The reported prevalence of pulmonary stenosis in TTTS is fourfold greater than in
non-TTTS. The proposed pathophysiology is that worsening right ventricular hypertrophy,
reduced right ventricular systolic function, and severe tricuspid regurgitation result in
progressively diminished flow across the pulmonic valve, resulting in stenosis or atresia and,
with increase severity, resulting in right ventricular outflow tract obstruction. The incidence
of right ventricular outflow tract obstruction in TTTS is as high as 9.6%. These observations
13

are not consistent with primary structural heart disease but rather acquired valvular
atresia/stenosis related to TTTS, a unique form of "acquired congenital" heart disease. As for
congenital heart diseases, there is a 15- to 23-fold higher risk of congenital heart disease with
TTTS over that of singletons, and a 2.78 times more frequent occurrence of congenital heart
disease in the setting of TTTS as compared to monochorionic twins without TTTS. The most
common structural heart defects in TTTS twins are ventricular septal defects and atrial septal
defects.
The development of TTTS in monochorionic, diamniotic gestations has significant
morbidity and mortality. Currently, most centers describe severity using only the Quintero
staging system. However, although recent reports have suggested that worsening Quintero
stage is associated with poorer outcomes following SFLP, the relationship between Quintero
stage and outcome remains controversial. The proposed Quintero staging assesses the
severity of TTTS, focuses on changes predominantly seen in the donor twin (DT). Findings
describing RT cardiomyopathy—although well described—are not incorporated into Quintero
staging, and thus, not incorporated into the formal assessment of disease severity. The more
advanced findings of elevated central venous pressure found in higher Quintero stages—
specifically, absence or reversal of venous flow during atrial contraction in the ductus
venosus or pulsatility in the umbilical vein—has been associated with poorer RT outcome,
suggesting a link between cardiovascular compromise and RT outcome.
There is association between recipient twin cardiovascular status and postnatal
survival. Although a relatively nonspecific predictor of recipient twin outcome, the CVPS
nonetheless serves as a tool characterize degree of cardiovascular derangement. As such, use
of the CVPS demonstrated that any cardiac findings, e.g., atrioventricular valve regurgitation,
cardiomegaly, or ventricular systolic dysfunction are associated with poorer RT outcome.
Moreover, as cardiac abnormalities "accumulate," outcomes are even worse. In the study’s
series, many of the cardiac findings resulting in deductions in CVPS were not venous
Doppler changes, and thereby would not be incorporated into assessment of disease severity
if applying the widely utilized Quintero staging, nor would they be assessed by standard
obstetric ultrasonography. Importantly, the data also demonstrated that Quintero staging did
not predict RT outcome in the study population.
A comprehensive fetal cardiac assessment by echocardiography may therefore be an
important component of clinical evaluation in pregnancies complicated by TTTS. For
example, inclusion of cardiac findings, such as those incorporated into the CVPS, may result
in a clinically useful modification of Quintero staging that could improve patient risk
14

stratification. The rate of progression during either expectant management or trial of
amnioreduction significantly correlated with the severity of recipient cardiomyopathy at
initial presentation. Early-stage TTTS may be better managed by an initial period of
expectant management or a trial of amnioreduction rather than proceeding directly to SFLP,
as long as there is no significant recipient-twin cardiomyopathy.
Recipient cardiomyopathy in TTTS is an adaptive fetal response to the hemodynamic,
hormonal and biochemical stressors associated with TTTS. Several reports have shown that
recipient cardiomyopathy is more common in more advanced stages of TTTS. Recently,
however, Michelfelder et al. showed, in a cross-sectional study of cardiac evaluation of 28
consecutive early-stage TTTS patients, significant cardiac changes in recipient twins ranging
between 7 and 64%. Moreover, Van Mieghem et al.18 also found, in an observational study
of early-stage TTTS (Stages I and II) that 70% had echocardiographic evidence of cardiac
dysfunction as well as elevated braintype natriuretic peptides, biomarkers of myocardial
strain. The findings in Habli's the study are consistent with these reports - i.e. that recipient
cardiomyopathy is common even in early stage TTTS, and the results suggest that even early
stage TTTS cases in fact constitute a heterogeneous population with a broad range of severity
of recipient cardiomyopathy, which may have a direct bearing on the natural history and
response to treatment. Such findings could explain the variable natural history of early-stage
TTTS cases.
The importance of fetal echocardiography in the assessment of the severity of TTTS
has been questioned by some groups. However, fetal echocardiographic assessment of TTTS
cardiomyopathy can be helpful in predicting not only the cases of TTTS that will progress
during expectant management or a trial of amnioreduction but also how fast it will progress.
Fetal echocardiography in conjunction with ultrasound findings, as used in the Cincinnati
staging system derived by Crombleholme, can be used to guide management options, assess
response to treatment and help in better understanding the pathophysiology of TTTS.
The incidence of recipient cardiomyopathy in early TTTS (Quintero Stages I and II) is
as high as 65%. Up to 46% of early-stage TTTS cases will remain stable or improve during
expectant management or a trial of amnioreduction, with significantly better fetal survival as
compared with those treated with primary SFLP. Conversely, 54% progressed within a mean
duration of 1.4 ± 1.5 weeks based on ultrasound and fetal echocardiographic parameters.
These findings provide proof of concept for the utility of fetal echocardiography in guiding
the management of early-stage TTTS.

15

CHAPTER IV
ECHOCARDIOGRAPHY IN TWIN-TO-TWIN TRANSFUSION SYNDROME 3,6
In the recipient twin, TTTS can lead to cardiovascular compromise, which can be
detected antenatally by ultrasound. On echocardiography, the most common abnormalities
seen in recipient twins are ventricular hypertrophy (18% to 49% of cases), increased
cardiothoracic ratio (as high as 47%), ventricular dilation (17% to 31%), tricuspid
regurgitation (35% to 52%), and mitral regurgitation (13% to 15%). In addition, cases of
acquired pulmonary stenosis/ atresia in the recipient twin have been reported. Other than rare
case reports, there are no autopsy studies of hearts in this population. Thus, the great majority
of cardiac abnormalities identified echocardiographically have not been corroborated.
A. Recipient Fetuses.
Up to 70%of recipient fetuses of TTTS show some echocardiographic sign of
cardiac compromiseat the time of diagnosis, either at the anatomical or at the functional
level. As such, in about half the cases, the heart is enlarged due to an increased
myocardial thickness rather than to ventricular dilatation. In terms of systolic function,
shortening fraction is considerably decreased in 30% of the recipients, and this
predominantly at the level of the right ventricle. Accordingly, speckle-trackingderivedmeasurements of strain and strain rate, although difficult to perform, show
decreased strain in the right ventricle of recipient fetuses of TTTS. In contrast to the
lower contractility and to earlier reports that did not show differences in cardiac output
between donors and recipients, two recent series in relatively large cohorts of recipient
fetuses have shown a moderate increase in cardiac output when corrections were made
for fetal weight. This finding clearly fits in with the volume overload theory.

16

Figure 1: Common echocardiographic findings in the recipient of TTTS. (a) Reversed
flow in the ductus venosus. (b) Umbilical vein pulsations. (c) Transverse view of the fetal
chest at the level of the 3-vessel view demonstrating forward flow in the aorta (blue) and
reversed flow in the ductus arteriosus and pulmonary artery (red) suggestive of functional
pulmonary atresia. (d) Doppler assessment at the level of the fetal 4-chamber view
demonstrating mitral and tricuspid regurgitation with the corresponding pulsed Doppler
spectrum below.
In TTTS, diastolic function is even more compromised than systolic function. As
a consequence of the thickened, dysfunctional myocardium, monophasic ventricular
filling patterns such as those seen in restrictive cardiomyopathy occur in about 20%–30%
of cases, again with a predominance on the right side. Moreover, we often observe a
shortening of the ventricular filling time, a prolongation of the isovolumetric relaxation
time and an increase in the Tei-index (which is a geometry independent indicator of both
systolic and diastolic function based on the assessment of the isovolumetric relaxation
and the isovolumetric contraction time). On average, the Tei-index is 40% higher than
normal and values above the upper limit of normal are observed in about 50% of cases.
Interpretation of the Tei-index in the fetal setting nevertheless deserves particular caution
as fetal blood pressure is often unknown and prolongation of the isovolumetric
contraction time can be a reflection of hypertension rather than of systolic dysfunction.
Therefore, separate analysis of the isovolumetric contraction and relaxation time is
justified, yet only technically possible at the level of the left ventricle due to the

17

implantation of the pulmonary and tricuspid valve precluding simultaneous recording of
the pulmonary and tricuspid flow.
Tricuspid regurgitation occurs in about 30%–50% of recipients but is severe in
only half of these. Mitral regurgitation on the other hand is much less frequent (6%–14%
of cases), yet usually severe (9%). The presence of valvular regurgitation allows to
estimate fetal blood pressure using the Bernouilli equation and studies have shown that
recipient fetuses display marked hypertension with systolic pressures over 2-fold the
normal value for gestational age.

Figure 2. Comparison of echocardiograms from recipient fetuses with and
without anomalous mitral arcade. Recipient fetuses with anomalous mitral arcade at
autopsy (A and B) or normal mitral valve at autopsy (C and D) had had prior
echocardiography studies that documented abnormal hemodynamics. Both hydropic
fetuses have evidence of severe tricuspid regurgitation, right atrial (RA) enlargement,
cardiomegaly, and skin edema; the fetus with anomalous mitral arcade has moderate
mitral regurgitation and left atrial (LA) enlargement, whereas the unaffected fetus has no
mitral regurgitation and a normal left atrium. LV indicates left ventricle; RV, right
ventricle.
Further down the vascular tree, Doppler assessment of the ductus venosus and the
umbilical venous flow allows to estimate the right atrial pressure curve. Reversed flow in
the ductus venosus and umbilical vein pulsations have been integrated in the Quintero
18

staging system and their presence upstages the disease to stage III. In most series from
tertiary referral centers, abnormal ductus venosus dopplers are seen in about 1 in 3
recipients and a pulsatile umbilical vein in 1 in 10.
It is important to note that in Quintero stage I, already 45% of cases show signs
of ventricular dysfunction in terms of an increased Tei index and that 35% of cases have
a fused right ventricular inflow pattern suggestive of diastolic dysfunction. Nevertheless,
left ventricular Tei-index and mitral and tricuspid regurgitation increase withQuintero
stage suggesting that theQuintero staging system, at least to some degree, reflects
progressive fetal cardiovascular compromise.
Changes in cardiac function are already present well before the actual
development of TTTS. As such, about 30%of fetuses withmoderate amniotic fluid
discordance not fulfilling the criteria of TTTS but ultimately progressing to the syndrome
show an increased myocardial performance index. Along the same line, 40% of
monochorionic twins that ultimately will develop TTTS have already abnormal findings
in the ductus venosus flow or discordant nuchal translucencymeasurements reflective of
altered hemodynamics in the first trimester of pregnancy. Unfortunately, these findings
are not very specific, nor very sensitive. They cannot therefore be used for early
prediction of the disease, nor should they be used to “upstage” (often benign) fluid
discordance to TTTS.

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Figure 3. Echocardiographic evidence of progression of mitral regurgitation. Case
4R at 19 3/7 weeks (A and B) and 23 5/7 weeks (C and D) shows progression of mitral
regurgitation (color frames) from trace to severe with associated development of left
atrial (LA) enlargement. Severe tricuspid regurgitation, right atrial (RA) enlargement,
cardiomegaly, and a pericardial effusion are also evident. LV indicates left ventricle; RV,
right ventricle.
Once a TTTS is fully installed, echocardiographic findings tend to progress over
time, with worsening ventricular hypertrophy and systolic dysfunction, which can
ultimately lead to fetal hydrops and intrauterine fetal demise.
Moreover,as growth of fetal cardiac structures is dependent on the blood flow
through them, persistent ventricular dysfunction can lead to secondary anatomic changes.
Consequently, in a consecutive series of 150 recipient fetuses, 16% had a smaller than
expected right ventricular outflow ract at the time of initial presentation. In up to 4%,
extreme right ventricular dysfunction can result in functional pulmonary atresia (Figure
1) with retrograde perfusion of the pulmonary trunk through the ductus arteriosus and
more rarely even in complete right heart flow reversal.
B. Donor Fetuses.
In contrast to recipient fetuses, donors seem to have a normal cardiac function,
yet some 5%–10% present with abnormal Doppler waveforms in the ductus venosus, and
3% with tricuspid regurgitation or umbilical vein pulsations, findings which are generally
explained by the presence of severe placental insufficiency. The latter is also supported
by an increased occurrence of abnormal diastolic flow in the umbilical artery in the donor
fetus.
Furthermore, although not significant in most studies, the donor twin has a trend
towards a lower Tei-index than in the normal population which is suggestive of
hypotension. Finally, there have been speculations about an increased incidence of aortic
coarctation in donors due to a lower venous return fromthe placenta and hence a
decreased loading of the left ventricular outflow tract.
C. Suspicion for Anomalous Mitral Arcade on Echocardiography
By ultrasound and echocardiographic assessment, more advanced Quintero stages
(3 and 4) and moderate to severe degrees of cardiovascular compromise were present in
both affected and unaffected twins. Recently, there has been heightened interest in the
cardiomyopathic changes that have been identified echocardiographically in recipient
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twins. Although anomalous mitral arcade may not be the only basis for heart failure in
TTTS, mitral regurgitation, left atrial enlargement, and left atrial hypertension can
contribute to the development of fetal hydrops. In addition, because right ventricular
systolic performance and diastolic performance are often compromisedin recipient
fetuses, the left ventricle may increase its contribution to combined ventricular output to
continue to meet the oxygen demands of the growing fetus. Significant alterations in left
ventricular performance have also been demonstrated in recipient twins; in this setting,
the development of severe mitral regurgitation may significantly limit the ability of the
left ventricle to contribute to combined ventricular output. Therefore, the findings from
our study underscore the importance of complete echocardiographic evaluation of the
fetal heart for evidence of cardiovascular compromise, including color Doppler for
evaluation of both mitral and tricuspid valves in pregnancies affected by TTTS. In
addition, we suggest that detection of significant regurgitation should raise the index of
suspicion for a structural abnormality of the valve. The prognostic significance of this
particular finding cannot be ascertained on the basis of this autopsy series and requires
further study. Nonetheless, previous reports have demonstrated an association of
atrioventricular valve regurgitation with considerably decreased recipient twin survival,
and in a prospective randomized trial of amnioreduction versus laser therapy for TTTS,
the most predictive model for recipient survival involved the use of a modified
cardiovascular profile score that uses observations of extent of recipient cardiac
dysfunction, including tricuspid and mitral valve regurgitation.

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CHAPTER V
SUMMARY

Cardiac dysfunction is a common finding in recipient fetuses and different new
“cardiac” staging systems have been proposed. Although they may bring new
pathophysiologic insights, their clinical value remains limited as they do not predict the
occurrence nor the outcome of the disease. However, further evaluation is necessary in stage I
disease, where equipoise is still present about the optimal treatment strategy. Additionally, the
impact of the decreased cardiac function on cerebral perfusion and longterm neurologic
development requires further investigation. Fetoscopic laser coagulation of the vascular
anastomoses interrupts the intertwin transfusion and has been shown to lead to fast
normalization of cardiac function. Nevertheless, recipients remain at increased risk of
pulmonary artery stenosis. Further work should be directed at detecting prenatally which
twins will have clinically important lesions at the time of birth.6
Ultrasound/echocardiographic evidence of left atrial dilation, mitral regurgitation, and
decreased mitral valve mobility should raise suspicion for anomalous mitral arcade. Marked
weight discordance on ultrasound might also indicate the development of anomalous mitral
arcade. This. Although uncommon, acquired mitral arcade is likely a physiologically
important lesion that may have prognostic significance in recipient twins, given the
previously described association of atrioventricular valve regurgitation with decreased
survival in this population.3
A thoughtful approach to the management of TTTS requires consideration of every
aspect

of

the

presentation

including

gestational

age,

stage,

Doppler

findings,

echocardiographic findings, concomitant placental insufficiency, and maternal risk factors.
Until we have an effective medical therapy for TTTS, a judicious application of invasive
procedures should be employed to optimize risk: benefit ratios for the mother and fetuses.4

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REFERENCES
1. U Herberg, et al. Long term cardiac follow up of severe twin to twin transfusion

syndrome after intrauterine laser coagulation. Heart 2006;92:95–100.
2. M.J. Raboisson, et al. Early Intertwin Differences in Myocardial Performance During

the Twin-to-Twin Transfusion Syndrome. Circulation. 2004;110:3043-3048.
3. Ursell Elizabeth Losada, et al. Anomalous Mitral Arcade in Twin-Twin Transfusion
Syndrome. Circulation. 2010;122:1456-1463.
4.
Colorado fetal care center. Twin-to-Twin Transfusion Syndrome. 2014.
http://coloradofetalcarecenter.childrenscolorado.org/
5. Society for Maternal-Fetal Medicine (SMFM). Twin-twin transfusion syndrome.

2013. http://dx.doi.org/10.1016/j.ajog.2012.10.880.
6. TimVanMieghem, et al. The Fetal Heart in Twin-to-Twin Transfusion Syndrome.
International Journal of Pediatrics. Volume 2010, Article ID 379792, 8 pages.
7. Fetoscopic Laser Therapy for Twin-Twin Transfusion Syndrome. Yao-Lung Chang.

Taiwanese J Obstet Gynecol 2006;45(4):294–301.
8. Twin–Twin Transfusion — As Good as It Gets? Nicholas M. Fisk and Paula Galea. n

engl j med 351;2:182-4.
9. Endoscopic Laser Surgery versus Serial Amnioreduction for Severe Twin-to-Twin
Transfusion Syndrome. Marie-Victoire Senat, et al. N Engl J Med 2004;351:136-44.
10. Short-term outcomes of fetoscopic laser surgery for severe twinetwin transfusion

syndrome from Taiwan single center experience: Demonstration of learning curve
effect on the fetal outcomes. Yao-Lung Chang, et al. Taiwanese Journal of Obstetrics
& Gynecology. 2012; 51: 350-3.

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