echocardiography in Twins

8/20/2019 echocardiography in Twins

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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 (80–00!) and a high

perinatal mor"idity and mortality. In TTTS# genetically identical twins are e$posed to

different haemodynamic conditions and environmental factors. %lacental vascular

anastomoses provide the anatomical "asis for the un"alanced intertwin transfusion from

donor to recipient. In the hypervolaemic recipient# cardiomegaly# "iventricular 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.

&ardiac dysfunction progresses with increasing gestational age. In addition# various types of

cardiac defects predominantly affecting the right ventricle and pulmonary artery have "een

reported. These include muscular right ventricular outflow o"struction# valvar pulmonary

stenosis and atresia# and left ventricular hypertrophic non'o"structive and o"structive

cardiomyopathy. In contrast# the hypovolaemic donor twin shows little cardiac pathology on

fetal echocardiography "ut does manifest increased afterload due to raised placental

resistance# as well as evidence of poor renal perfusion.

oth fetuses are at risk of death and of short' and long'term cardiocirculatory

complications# which have "een reported to decrease when early treatment is provided.

nfortunately# early in the process# TTTS is difficult to differentiate from intrauterine growth

restriction (I*+) due to placental circulatory insufficiency, at this stage# discordances in

fetal growth and amniotic fluid volumes are first signs shared "y "oth conditions. -uring the

course of TTTS# hypertrophic cardiomyopathy is o"served in the recipient twin, its

pathogenesis remains unclear. %ressure 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# su"clinical evidence of cardiac dysfunction could "e among the first signs o"served

with TTTS# whereas in I*+# no difference in myocardial performance should "e e$pected#

at least early in the process when impairment in fetal o$ygenation is still well compensated.

Twin'twin transfusion syndrome (TTTS) occurs in 0! to 0! of mono/ygous twin

gestations and is an important cause of perinatal mortality in monochorionic twins with very

high mortality rates if untreated. The syndrome is characteri/ed clinically "y polyhydramnios

in twin and oligohydramnios in the other. The pathophysiology of the syndrome is

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incompletely understood, however# it has "een speculated that an im"alance in net "lood

supply to the recipient fetus resulting from a"normal placental vascular connections#

com"ined with e$posure to circulating a"normal vasoactive mediators# produces the

syndrome. In the recipient twin# TTTS can lead to cardiovascular compromise# which can "e

detected antenatally "y ultrasound. n echocardiography# the most common a"normalities

seen in recipient twins are ventricular hypertrophy (8! to 12! of cases)# increased

cardiothoracic ratio (as high as 13!)# ventricular dilation (3! to 4!)# tricuspid

regurgitation (45! to 5!)# and mitral regurgitation (4! to 5!). In addition# cases of

ac6uired pulmonary stenosis7atresia in the recipient twin have "een reported. 4

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CHAPTER II

TWIN-TO-TWIN TRANSFUSION SYNDROME5#3#8

anagement of Twin'Twin Transfusion Syndrome (TTTS) is one of the most

challenging clinical pro"lems concerning multiple gestations. 9ppro$imately 0 percent of

all twin pregnancies are monochorionic# and the incidence of TTTS in monochorionic

diamniotic gestations is appro$imately 5 to 5 percent. TTTS is a phenomenon almost

e$clusive to monochorionic pregnancies.

The natural history of severe TTTS is well esta"lished with mortality rates approaching 80 to

00 percent if left untreated# especially when it presents prior to 0 weeks gestation in which

case it tends to "e more severe and more rapidly progressive. This is particularly trou"lesome

given that two structurally normal fetuses are involved.

Twin'twin transfusion syndrome (TTTS) is diagnosed prenatally "y ultrasound. The

-iagnosis re6uires criteria: () the presence of amonochorionic diamniotic (&-9)

pregnancy, and () the presence of oligohydramnios (de;ned as a ma$imal vertical pocket

of ?cm) in one sac# and of polyhydramnios (a =% of @8 cm) in the other sac

(Aigure ). =% of cm and 8 cm represent the 5th and 25th percentiles for amniotic Buid

measurements# respectively# and the presence of "oth is used to de;ne stage I TTTS. If there

is a su"Cective difference in amniotic Buid in the sacs that fails to meet these criteria# pro'

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gression to TTTS occurs in ?5! of cases. 9lthough growth discordance (usually de;ned as

@0!) and intrauterine growth restriction (I*+) (estimated fetal weight ?0!for

gestational age) often complicate TTTS# growth discordance itself or I*+ itself are not

diagnostic criteria. The differential diagnosis may include selective I*+# or possi"ly an

anomaly in twin causing amniotic Buid a"normality.

Twin anemia'polycythemia se6uence (T9%S) has "een recently descri"ed in&-9

gestations# and is de;ned as the presence of anemia in the donor and polycythemia in the

recipient# diagnosed antenatally "y middle cere"ral artery (&9)–peak systolic velocity

(%S=) @.5 multiples of median in the donor and &9 %S= ?.0 multiples of median in the

recipient# in the a"sence of oligohydramnios polyhydramnios.

The most commonly used TTTS staging systemwas developed "yDuintero et al in

222# and is "ased on sonographic ;ndings. The TTTS Duintero staging system includes 5

stages# ranging from mild disease with isolated discordant amniotic Buid volume to severe

disease with demise of one or "oth twins (Ta"le and Aigures and 4). This system has some

prognostic signi;cance and provides a method to compare outcome data using different

therapeutic interventions. 9lthough the stages do not correlate perfectly with perinatal

survival# it is relatively straightforward to apply#may improve communication "etween

patients and providers# and identi;es the su"set of cases most likely to "ene;t from treatment.

Since the development of the Duintero staging system# much has "een learned a"out the

changes in fetal cardiovascular physiology that accompany disease progression (discussed

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"elow). yocardial performance a"normalities have "een descri"ed# particularly in recipient

twins# including those with only stage I or II TTTS.

9ppro$imately one'third of twins are mono/ygotic (E)# and three'fourths of E

twins are &-9. In general# only twin gestations with &-9 placentation are at signi;cant

risk for TTTS# which complicates a"out 8'0! of &-9 pregnancies. TTTS is very

uncommon in E twins with dichorionic or monoamniotic placentation. 9lthough most twins

conceived with in vitro fertili/ation (I=A) are dichorionic# it is important to remem"er that

there is a ' to 'fold increase in E twinning in em"ryos conceived with I=A# and

TTTS can therefore occur for I=A &-9 pregnancies.

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In current practice# the prevalence of TTTS is appro$imately '4 per 0#000 "irths.

The presentation of TTTS is highly varia"le. ecause pregnancieswith TTTS often receive

care at referral centers# data a"out the stage of TTTS at initial presentation (ie# to nonreferral

centers) are lacking in the literature. Aetal therapy centers report that a"out '5!of their

cases at referral were Duintero stage I (pro"a"ly underestimated as some referral centers did

not report stage I TTTS cases)# 0'10! were stage II# 48'F0! were stage III# F'3! were

stage I=# and !were stage =.

9lthough TTTS may develop at any time in gestation# the maCority of cases are

diagnosed in the second trimester. Stage I may progress to a nonvisuali/ed fetal "ladder in the

donor (stage II) (Aigure )# and a"sent or reversed end'diastolic Bow in the um"ilical artery of

donor or recipient twins may su"se6uently develop (stage III) (Aigure 4)# followed "y

hydrops (stage I=). Gowever# TTTS often does not progress in a predicta"le manner. Hatural

history data "y stage are limited# especially for stages II'=# as staging was initially proposed

in 222. This is "ecause most natural history data were pu"lished "efore 222# and

thereforewas not strati;ed "y stage (Ta"le ).

Underlying Pathohy!iology

The primary etiologic pro"lem 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. =irtually all&-9 placentas have anastomoses that link the

circulations of the twins# yet not all &-9 twins develop TTTS. There are 4 main types of

anastomoses in monochorionic placentas: venovenous (==)# arterioarterial (99)# and

arteriovenous (9=). 9= anastomoses are found in 20'25! of &-9 placentas# 99 in 85'

20!# and == in 5'0!.

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oth 99 and == anastomoses are direct super;cial connections on the surface of the

placenta with the potential for "idirectional Bow (Aigure 1). In 9= anastomoses# while the

vessels themselves are on the surface of the placenta# the actual anastomotic connections

occur in a cotyledon# deep within the placenta (Aigure 1).9=anastomoses can result in

unidirectional Bow fromone twin to the other# and if uncompensated#may lead to an

im"alance of volume "etween the twins. nlike 99 and ==# which are direct vessel'to'vessel

connections# 9= connections are linked through large capillary "eds deepwithin the

cotyledon.

9= anastomoses are usually multiple and overall "alanced in "oth directions so that

TTTS does not occur. hile the num"er of 9= anastomoses from donor to recipient may "e

important# their si/e aswell as placental resistance likely inBuences the volume of intertwin

transfusion that occurs. %lacentas in twins affected with TTTS are reportedly more likely to

have ==# "ut less likely to have 99 anastomoses. It is thought that these "idirectional

anastomoses may compensate for the unidirectional Bow through 9= connections# there"y

preventing the development of TTTS or decreasing its severitywhen it does occur.

ortality is highest in the a"sence of 99 and lowest when these anastomoses are

present (1! vs 5!). Gowever# the presence of 99 is not completely protective# as a"out

5'40!of TTTS casesmay also have these anastomoses. The im"alance of "lood Bow

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 "e additional factors "eyond placentalmorphology#

such as comple$ interactions of the renin'angiotensin systemin the twins# involved in thedevelopment of this disorder.

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Manage"ent

The management options descri"ed for TTTS include e$pectant management#

amnioreduction# intentional septostomy of the intervening mem"rane# fetoscopic laser

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photocoagulation of placental anastomoses# and selective reduction. The interventions that

have "een evaluated in randomi/ed controlled trials (+&Ts) include intentional septostomy of

the intervening mem"rane to e6uali/e the Buid in "oth sacs# amnioreduction of the e$cess

Buid in the recipientJs sac# and laser a"la tion of placental anastomoses. There have "een 4

randomi/ed trials designed to evaluate some of the different treatment modalities for TTTS#

all of which were terminated prior to recruitment of the planned su"Cect num"er after in'

terim analyses# as discussed "elow. -espite the limitations and early termination of these

clinical trials# they represent the "est availa"le data upon which to Cudge the various

treatments for TTTS &onsultation 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 twin# and# if availa"le# long'term outcomes of the

"a"ies# including neurologic outcome. K$tensive counseling should "e provided to patients

with pregnancies complicated "y TTTS# including natural history of the disease# as well as

management options and their risks and "ene;ts.

K$pectant management involves no intervention. This natural history of TTTS# also

called conservative management# has limited outcome data according to stage# particularly

for advanced disease (Ta"le ). It is important that the limitations in the availa"le data are

discussed with the patient with TTTS# and compared with availa"le outcome data for

interventions.

9mnioreduction involves the removal of amniotic Buid from the polyhydram'

niotic sac of the recipient. It is usually done only when the=% is @8 cm# with an aim to

correct it to a =% of ?8 cm# often to ?5cm or ?F cm. sually an 8 or 0 gauge needle is

used. Some practitioners use aspiration with syringes# while some use vacuum containers.

9mnioreduction can "e performed either as a 'time procedure# as t times this can resolve

stage I or II TTTS# or serially# eg# every time the=% s @8 cm. It can "e performed any time

@1 weeks. 9mnioreduction is hypothisi/ed to reduce the intraamniotic and placental

intravascular pressures# potentially facilitating placental "lood Bow# and7or to possi"ly reduce

the incidence of preterm la"or and "irth related to polyhydramnios. 9mnioreduction may

"e used also @F weeks# particularly in cases with maternal respiratory distress or preterm

contractions from polyhydramnios. 9mnioreduction has "een associated with average

survival rates of 50!# with large registries reporting F0'F5! overall survival. Gowever# serial

amnioreduction is often necessary# and repeated procedures increase the likelihood of

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complications such as preterm premature rupture of themem"ranes# preterm la"or# a"ruption#

infection# and fetal death. 9nother consideration is that any invasive procedure prior to

fetoscopy may decrease the feasi"ility and success of laser due to "leeding# chorioamnion

separation# inadvertent septostomy# or mem"rane rupture.

Septostomy involves intentionally puncturing with a needle the amniotic mem"ranes

"etween the &-9 sacs# theoretically allowing e6uili"ration of amniotic Buid volume in

the sacs. In the randomi/ed trial in which it was evaluated# the intertwin mem"rane was

purposefully perforated under ultrasound guidance with a single puncture using a 'gauge

needle. This was usually introduced through the donorJs twin gestational sac into the

recipient twinJs amniotic cavity. If reaccumulation of amniotic Buid in the donor twin sac was

not seen in a"out 18 hours# a repeat septostomy was undertaken. Intentional septostomy is

mentioned only to note that it has generally "een a"andoned as a treatment for TTTS. It is

"elieved to offer no signi;cant therapeutic advantage# and may lead to disruption of the

mem"rane and a functional monoamniotic situation. 9 randomi/ed trial of amnioreduction vs

septostomy ended after an interimanalysis found that the rate of survival of at least twin

was similar "etween the groups# and that recruitment had "een slower than anticipated. In

all# 23! of the enrolled pregnancies had stages I'III TTTS# and results were not otherwise

reported "y stage. In 10! of the septostomy cases# additional procedures were needed. Ho

data on neurologic outcome are availa"le.

Laser involves photocoagulating the vascular anastomoses crossing from one side of

the placenta to the other. This is usually performed "y placing a sheath and passing an

endoscope under ultrasound guidance. ltrasound 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 a"lation is to functionally separate the placenta into regions# each

supplying one of the twins. This unlinking of the circulations of the twins is often referred to

as Mdichorioni/ationN of the monochorionic placenta. 9de6uate visuali/ation of the vascular

e6uator that separates the cotyledons of one twin from the other is critical for laser

photocoagulation. Selective coagulation of 9= as well as 99 and == anastomoses is

preferred over nonselective a"lation of all vessels crossing the separating mem"rane as it

appears to lead to fewer procedure'related fetal losses. Se6uential coagulation of the donor

artery to recipient vein followed "y recipient artery to donor vein may theoretically allow

some return of Buid fromthe recipient to the donor prior to severing other connections.

&riteria for laser have included &-9 pregnancies "etween a"out 5'F weeks with the

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recipient twin having =% O8.0 cm at P0 weeks or O0.0cm at @0 weeks and a distended

fetal "ladder# and donor twin having =% P.0 cm in trial# and &-9 pregnancies at ? 1

weeks with the recipient twin having =% @8 cm# and donor twin having =% Pcm and

nonvisuali/ed fetal "ladder in the other. There is insuf;cient evidence to recommend

management in&-9 pairs with TTTS in higher'order multiple gestations# "ut laser has

"een proposed as feasi"le and effective.

Selective reduction involves purposefully interrupting um"ilical cord "lood Bow of

twin# causing the death of this twin# with the purpose of improving the outcome of the other

surviving twin. sually the cord occlusion is performed with radiofre6uency a"lation or cord

coagulation# "ut other procedures have "een employed. "viously this option can "e

associated with a ma$imum of 50! overall survival# so# if ever considered# it is usually

reserved for stages III or I= TTTS only.

Antenatal Monitoring #or Pregnan$ie! Co"li$ated %y TTTS

There are no randomi/ed trials to evaluate the effectiveness of antenatal monitoring

for pregnancies complicated "y TTTS. eekly monitoring of the um"ilical artery -oppler

Bow and =% of amniotic Buid of each fetus may "e considered. The evidence for

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effectiveness of serial (eg# weekly or twice7wk) nonstress tests# "iophysical pro;les# and other

antenatal testing modalities is insuf;cient to make a recommendation# "ut these tests can "e

considered. ne reason for surveillance# even following laser therapy# is that not all

anastomoses are a"lated at the time of laser. +esidual anastomoses# either initially undetected#

missed# or revasculari/ed after laser# have "een o"served in up to a third of cases. %lacental

casting has also demonstrated the presence of deep# atypical 9= anastomoses "eneath the

chorionic plate thatwould not "e visi"le "y fetoscopy. Aailure to coagulate all 9=

anastomoses can lead to persistent# recurrent or reversed TTTS. %ersistent or recurrent TTTS

has "een reported in 1!of cases postlaser and reversed TTTS# with the recipient "ecoming

anemic and the donor polycythemic# in 4! of cases. hile T9%S can occur spontaneously

in a &-9 gestation# it is a known iatrogenic complication of laser.

Screening "y transvaginal ultrasound for short cervical length in TTTS cases has also

"een proposed# as this is associated with preterm "irth# a known complication of TTTS. 9s

there are no interventions shown to improve outcome "ased on short transvaginal ultrasound

cervical length in TTTS cases# this screening cannot "e recommended at this time.

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CHAPTER III

CARDIOMYOPATI IN TWIN-TO-TWIN TRANSFUSION SYNDROME1

&ardiovascular compromise occurs in most recipient twins# is a maCor cause of death

for these fetuses# and contri"utes to mor"idity and mortality in the donor cotwin. 9s early as

22# specific recipient echocardiographic a"normalities were reported. These a"normalities

are tricuspid regurgitation# ventricular hypertrophy# increased cardiothoracic ratio# and

pulmonary stenosis. 9n echocardiographic e$amination 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. 9t first# right ventricular dilatation

and hypertrophy can "e identified to a greater degree than ventricular dilatation and

hypertrophy in the left ventricle. Gowever# as the process progresses# right and left

ventricular hypertrophy "ecome more pronounced. This hypertrophy is associated with

atrioventricular valve regurgitation involving first tricuspid regurgitation and then mitral

valve regurgitation. Kstimates of right ventricular pressures "ased on flow velocity of

tricuspid regurgitation Cet suggest that recipient cardiomyopathy is a hypertensive

cardiomyopathy. +ight ventricular pressures in e$cess of 30 mm Gg are common. The cause

of this hypertensive cardiomyopathy is postulated to "e due to vasoactive su"stances from the

placenta or donor twin. The recipient twin e$periences an increase in "lood volume#

vasoconstriction# and ventricular hypertrophy# possi"ly mediated "y angiotensin II and

endothelin'.

The most common recipient cardiovascular a"normalities in TTTS are unilateral or

"ilateral ventricular hypertrophy (ranges 8!'12!)# increased cardiothoracic ratio as high as

13!# ventricular dilation (ranges 3!'4!)# tricuspid regurgitation (ranges 45!'5!)# and

mitral regurgitation (ranges 4!'5!). These a"normalities are more common with

advanced stages of disease. Ainally# several cases of ac6uired pulmonary atresia7stenosis with

intact ventricular septum have "een descri"ed 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 o"struction. The incidence

of right ventricular outflow tract o"struction in TTTS is as high as 2.F!. These o"servations

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are not consistent with primary structural heart disease "ut rather ac6uired valvular

atresia7stenosis related to TTTS# a uni6ue form of Qac6uired congenitalQ heart disease. 9s for

congenital heart diseases# there is a 5' to 4'fold higher risk of congenital heart disease with

TTTS over that of singletons# and a .38 times more fre6uent 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

mor"idity and mortality. &urrently# most centers descri"e severity using only the Duintero

staging system. Gowever# although recent reports have suggested that worsening Duintero

stage is associated with poorer outcomes following SAL%# the relationship "etween Duintero

stage and outcome remains controversial. The proposed Duintero staging assesses the

severity of TTTS# focuses on changes predominantly seen in the donor twin (-T). Aindings

descri"ing +T cardiomyopathyRalthough well descri"edRare not incorporated into Duintero

staging# and thus# not incorporated into the formal assessment of disease severity. The more

advanced findings of elevated central venous pressure found in higher Duintero stagesR

specifically# a"sence or reversal of venous flow during atrial contraction in the ductus

venosus or pulsatility in the um"ilical veinRhas "een associated with poorer +T outcome#

suggesting a link "etween cardiovascular compromise and +T outcome.

There is association "etween recipient twin cardiovascular status and postnatal

survival. 9lthough a relatively nonspecific predictor of recipient twin outcome# the &=%S

nonetheless serves as a tool characteri/e degree of cardiovascular derangement. 9s such# use

of the &=%S demonstrated that any cardiac findings# e.g.# atrioventricular valve regurgitation#

cardiomegaly# or ventricular systolic dysfunction are associated with poorer +T outcome.

oreover# as cardiac a"normalities Qaccumulate#Q outcomes are even worse. In the studyJs

series# many of the cardiac findings resulting in deductions in &=%S were not venous

-oppler changes# and there"y would not "e incorporated into assessment of disease severity

if applying the widely utili/ed Duintero staging# nor would they "e assessed "y standard

o"stetric ultrasonography. Importantly# the data also demonstrated that Duintero staging did

not predict +T outcome in the study population.

9 comprehensive fetal cardiac assessment "y echocardiography may therefore "e an

important component of clinical evaluation in pregnancies complicated "y TTTS. Aor

e$ample# inclusion of cardiac findings# such as those incorporated into the &=%S# may result

in a clinically useful modification of Duintero staging that could improve patient risk

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stratification. The rate of progression during either e$pectant management or trial of

amnioreduction significantly correlated with the severity of recipient cardiomyopathy at

initial presentation. Karly'stage TTTS may "e "etter managed "y an initial period of

e$pectant management or a trial of amnioreduction rather than proceeding directly to SAL%#

as long as there is no significant recipient'twin cardiomyopathy.

+ecipient cardiomyopathy in TTTS is an adaptive fetal response to the hemodynamic#

hormonal and "iochemical stressors associated with TTTS. Several reports have shown that

recipient cardiomyopathy is more common in more advanced stages of TTTS. +ecently#

however# ichelfelder et al. showed# in a cross'sectional study of cardiac evaluation of 8

consecutive early'stage TTTS patients# significant cardiac changes in recipient twins ranging

"etween 3 and F1!. oreover# =an ieghem et al.8 also found# in an o"servational study

of early'stage TTTS (Stages I and II) that 30! had echocardiographic evidence of cardiac

dysfunction as well as elevated "raintype natriuretic peptides# "iomarkers of myocardial

strain. The findings in Ga"lis 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 "road range of severity

of recipient cardiomyopathy# which may have a direct "earing on the natural history and

response to treatment. Such findings could e$plain the varia"le natural history of early'stage

TTTS cases.

The importance of fetal echocardiography in the assessment of the severity of TTTS

has "een 6uestioned "y some groups. Gowever# fetal echocardiographic assessment of TTTS

cardiomyopathy can "e helpful in predicting not only the cases of TTTS that will progress

during e$pectant management or a trial of amnioreduction "ut also how fast it will progress.

Aetal echocardiography in conCunction with ultrasound findings# as used in the &incinnati

staging system derived "y &rom"leholme# can "e used to guide management options# assess

response to treatment and help in "etter understanding the pathophysiology of TTTS.

The incidence of recipient cardiomyopathy in early TTTS (Duintero Stages I and II) is

as high as F5!. p to 1F! of early'stage TTTS cases will remain sta"le or improve during

e$pectant management or a trial of amnioreduction# with significantly "etter fetal survival as

compared with those treated with primary SAL%. &onversely# 51! progressed within a mean

duration of .1 .5 weeks "ased 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.

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CHAPTER I&

ECHOCARDIO'RAPHY IN TWIN-TO-TWIN TRANSFUSION SYNDROME()*

In the recipient twin# TTTS can lead to cardiovascular compromise# which can "e

detected antenatally "y ultrasound. n echocardiography# the most common a"normalities

seen in recipient twins are ventricular hypertrophy (8! to 12! of cases)# increased

cardiothoracic ratio (as high as 13!)# ventricular dilation (3! to 4!)# tricuspid

regurgitation (45! to 5!)# and mitral regurgitation (4! to 5!). In addition# cases of

ac6uired pulmonary stenosis7 atresia in the recipient twin have "een reported. ther than rare

case reports# there are no autopsy studies of hearts in this population. Thus# the great maCority

of cardiac a"normalities identified echocardiographically have not "een corro"orated.

A+ Re$iient Fet,!e!+

p to 30!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. 9s such# in a"out 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 considera"ly decreased in 40! of the recipients# and this

predominantly at the level of the right ventricle. 9ccordingly# speckle'tracking'

derivedmeasurements 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 diff erences in cardiac output

"etween 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 ;nding clearly ;ts in with the volume overload theory.

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Aigure : &ommon echocardiographic ;ndings in the recipient of TTTS. (a) +eversed

Bow in the ductus venosus. (") m"ilical vein pulsations. (c) Transverse view of the fetal

chest at the level of the 4'vessel view demonstrating forward Bow in the aorta ("lue) and

reversed Bow in the ductus arteriosus and pulmonary artery (red) suggestive of functional

pulmonary atresia. (d) -oppler assessment at the level of the fetal 1'cham"er view

demonstrating mitral and tricuspid regurgitation with the corresponding pulsed -oppler

spectrum "elow.

In TTTS# diastolic function is even more compromised than systolic function. 9s

a conse6uence of the thickened# dysfunctional myocardium# monophasic ventricular

;lling patterns such as those seen in restrictive cardiomyopathy occur in a"out 0!–40!

of cases# again with a predominance on the right side. oreover# we often o"serve a

shortening of the ventricular ;lling time# a prolongation of the isovolumetric rela$ation

time and an increase in the Tei'inde$ (which is a geometry independent indicator of "oth

systolic and diastolic function "ased on the assessment of the isovolumetric rela$ation

and the isovolumetric contraction time). n average# the Tei'inde$ is 10! higher than

normal and values a"ove the upper limit of normal are o"served in a"out 50! of cases.

Interpretation of the Tei'inde$ in the fetal setting nevertheless deserves particular caution

as fetal "lood pressure is often unknown and prolongation of the isovolumetric

contraction time can "e a reBection of hypertension rather than of systolic dysfunction.

Therefore# separate analysis of the isovolumetric contraction and rela$ation time is

Custi;ed# yet only technically possi"le at the level of the left ventricle due to the

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implantation of the pulmonary and tricuspid valve precluding simultaneous recording of

the pulmonary and tricuspid Bow.

Tricuspid regurgitation occurs in a"out 40!–50! of recipients "ut is severe in

only half of these. itral regurgitation on the other hand is much less fre6uent (F!–1!

of cases)# yet usually severe (2!). The presence of valvular regurgitation allows to

estimate fetal "lood pressure using the ernouilli e6uation and studies have shown that

recipient fetuses display marked hypertension with systolic pressures over 'fold the

normal value for gestational age.

Aigure . &omparison of echocardiograms from recipient fetuses with and

without anomalous mitral arcade. +ecipient fetuses with anomalous mitral arcade at

autopsy (9 and ) or normal mitral valve at autopsy (& and -) had had prior echocardiography studies that documented a"normal hemodynamics. oth hydropic

fetuses have evidence of severe tricuspid regurgitation# right atrial (+9) enlargement#

cardiomegaly# and skin edema, the fetus with anomalous mitral arcade has moderate

mitral regurgitation and left atrial (L9) enlargement# whereas the unaffected fetus has no

mitral regurgitation and a normal left atrium. L= indicates left ventricle, +=# right

ventricle.

Aurther down the vascular tree# -oppler assessment of the ductus venosus and the

um"ilical venous Bow allows to estimate the right atrial pressure curve. +eversed Bow in

the ductus venosus and um"ilical vein pulsations have "een integrated in the Duintero

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staging system and their presence upstages the disease to stage III. In most series from

tertiary referral centers# a"normal ductus venosus dopplers are seen in a"out in 4

recipients and a pulsatile um"ilical vein in in 0.

It is important to note that in Duintero stage I# already 15! of cases show signs

of ventricular dysfunction in terms of an increased Tei inde$ and that 45! of cases have

a fused right ventricular inBow pattern suggestive of diastolic dysfunction. Hevertheless#

left ventricular Tei'inde$ and mitral and tricuspid regurgitation increase withDuintero

stage suggesting that theDuintero staging system# at least to some degree# reBects

progressive fetal cardiovascular compromise.

&hanges in cardiac function are already present well "efore the actual

development of TTTS. 9s such# a"out 40!of fetuses withmoderate amniotic Buid

discordance not ful;lling the criteria of TTTS "ut ultimately progressing to the syndrome

show an increased myocardial performance inde$. 9long the same line# 10! of

monochorionic twins that ultimately will develop TTTS have already a"normal ;ndings

in the ductus venosus Bow or discordant nuchal translucencymeasurements reBective of

altered hemodynamics in the ;rst trimester of pregnancy. nfortunately# these ;ndings

are not very speci;c# nor very sensitive. They cannot therefore "e used for early

prediction of the disease# nor should they "e used to MupstageN (often "enign) Buid

discordance to TTTS.

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Aigure 4. Kchocardiographic evidence of progression of mitral regurgitation. &ase

1+ at 2 473 weeks (9 and ) and 4 573 weeks (& and -) shows progression of mitral

regurgitation (color frames) from trace to severe with associated development of left

atrial (L9) enlargement. Severe tricuspid regurgitation# right atrial (+9) enlargement#

cardiomegaly# and a pericardial effusion are also evident. L= indicates left ventricle, +=#

right ventricle.

nce a TTTS is fully installed# echocardiographic ;ndings tend to progress over

time# with worsening ventricular hypertrophy and systolic dysfunction# which can

ultimately lead to fetal hydrops and intrauterine fetal demise.

oreover#as growth of fetal cardiac structures is dependent on the "lood Bow

through them# persistent ventricular dysfunction can lead to secondary anatomic changes.

&onse6uently# in a consecutive series of 50 recipient fetuses# F! had a smaller than

e$pected right ventricular outBow ract at the time of initial presentation. In up to 1!#

e$treme right ventricular dysfunction can result in functional pulmonary atresia (Aigure

) with retrograde perfusion of the pulmonary trunk through the ductus arteriosus and

more rarely even in complete right heart Bow reversal.

. -onor Aetuses.

In contrast to recipient fetuses# donors seem to have a normal cardiac function#

yet some 5!–0! present with a"normal -oppler waveforms in the ductus venosus# and

4! with tricuspid regurgitation or um"ilical vein pulsations# ;ndings which are generally

e$plained "y the presence of severe placental insufficiency. The latter is also supported

"y an increased occurrence of a"normal diastolic Bow in the um"ilical artery in the donor

fetus.

Aurthermore# although not signi;cant in most studies# the donor twin has a trend

towards a lower Tei'inde$ than in the normal population which is suggestive of

hypotension. Ainally# there have "een speculations a"out 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 outBow tract.

&. Suspicion for 9nomalous itral 9rcade on Kchocardiography

y ultrasound and echocardiographic assessment# more advanced Duintero stages

(4 and 1) and moderate to severe degrees of cardiovascular compromise were present in

"oth affected and unaffected twins. +ecently# there has "een heightened interest in the

cardiomyopathic changes that have "een identified echocardiographically in recipient

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twins. 9lthough anomalous mitral arcade may not "e the only "asis for heart failure in

TTTS# mitral regurgitation# left atrial enlargement# and left atrial hypertension can

contri"ute to the development of fetal hydrops. In addition# "ecause right ventricular

systolic performance and diastolic performance are often compromisedin recipient

fetuses# the left ventricle may increase its contri"ution to com"ined ventricular output to

continue to meet the o$ygen demands of the growing fetus. Significant alterations in left

ventricular performance have also "een demonstrated in recipient twins, in this setting#

the development of severe mitral regurgitation may significantly limit the a"ility of the

left ventricle to contri"ute to com"ined 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 -oppler for

evaluation of "oth mitral and tricuspid valves in pregnancies affected "y TTTS. In

addition# we suggest that detection of significant regurgitation should raise the inde$ of

suspicion for a structural a"normality of the valve. The prognostic significance of this

particular finding cannot "e ascertained on the "asis of this autopsy series and re6uires

further study. Honetheless# previous reports have demonstrated an association of

atrioventricular valve regurgitation with considera"ly decreased recipient twin survival#

and in a prospective randomi/ed 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 o"servations of e$tent of recipient cardiac

dysfunction# including tricuspid and mitral valve regurgitation.

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CHAPTER &

SUMMARY

&ardiac dysfunction is a common ;nding in recipient fetuses and diff erent new

McardiacN staging systems have "een proposed. 9lthough they may "ring new

pathophysiologic insights# their clinical value remains limited as they do not predict the

occurrence nor the outcome of the disease. Gowever# further evaluation is necessary in stage I

disease# where e6uipoise is still present a"out the optimal treatment strategy. 9dditionally# the

impact of the decreased cardiac function on cere"ral perfusion and longterm neurologic

development re6uires further investigation. Aetoscopic laser coagulation of the vascular

anastomoses interrupts the intertwin transfusion and has "een shown to lead to fast

normali/ation of cardiac function. Hevertheless# recipients remain at increased risk of

pulmonary artery stenosis. Aurther work should "e directed at detecting prenatally which

twins will have clinically important lesions at the time of "irth. F

ltrasound7echocardiographic evidence of left atrial dilation# mitral regurgitation# and

decreased mitral valve mo"ility should raise suspicion for anomalous mitral arcade. arked

weight discordance on ultrasound might also indicate the development of anomalous mitral

arcade. This. 9lthough uncommon# ac6uired mitral arcade is likely a physiologically

important lesion that may have prognostic significance in recipient twins# given the

previously descri"ed association of atrioventricular valve regurgitation with decreased

survival in this population.4

9 thoughtful approach to the management of TTTS re6uires consideration of every

aspect of the presentation including gestational age# stage# -oppler findings#

echocardiographic findings# concomitant placental insufficiency# and maternal risk factors.

ntil we have an effective medical therapy for TTTS# a Cudicious application of invasive

procedures should "e employed to optimi/e risk: "enefit ratios for the mother and fetuses.1

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REFERENCES

1. Ger"erg# et al. Long term cardiac follow up of severe twin to twin transfusion

syndrome after intrauterine laser coagulation. Geart 00F,2:25–00.

2. .U. +a"oisson# et al. Karly Intertwin -ifferences in yocardial %erformance -uring

the Twin'to'Twin Transfusion Syndrome. &irculation. 001,0:4014'4018.

3. rsell Kli/a"eth Losada# et al. 9nomalous itral 9rcade in Twin'Twin Transfusion

Syndrome. &irculation. 00,:15F'1F4.

4. &olorado fetal care center. Twin'to'Twin Transfusion Syndrome. 01.

http:77coloradofetalcarecenter.childrenscolorado.org7

5. Society for aternal'Aetal edicine (SA). Twin'twin transfusion syndrome.

04. http:77d$.doi.org70.0F7C.aCog.0.0.880.

6. Tim=anieghem# et al. The Aetal Geart in Twin'to'Twin Transfusion Syndrome.International Uournal of %ediatrics. =olume 00# 9rticle I- 43232# 8 pages.

7. Aetoscopic Laser Therapy for Twin'Twin Transfusion Syndrome. Vao'Lung &hang.

Taiwanese U "stet *ynecol 00F,15(1):21–40.

8. Twin–Twin Transfusion R 9s *ood as It *etsW Hicholas . Aisk and %aula *alea. n

engl C med 45,:8'1.

9. Kndoscopic Laser Surgery versus Serial 9mnioreduction for Severe Twin'to'Twin

Transfusion Syndrome. arie'=ictoire Senat# et al. H Kngl U ed 001,45:4F'11.

10. Short'term outcomes of fetoscopic laser surgery for severe twinetwin transfusion

syndrome from Taiwan single center e$perience: -emonstration of learning curve

effect on the fetal outcomes. Vao'Lung &hang# et al. Taiwanese Uournal of "stetrics

X *ynecology. 0, 5: 450'4.

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