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The TwinTwin
Transfusion Syndrome
VENU JAIN, MD, PhD and
NICHOLAS M. FISK, PhD, FRCOG
Center for Fetal Care, Queen Charlottes and Chelsea Hospital,
Institute of Reproductive and Developmental Biology, Imperial
College London, London, UK
Correspondence: Dr. Venu Jain, Clinical Lecturer in Obstetrics and Gynaecology, Institute of Reproductive &
Developmental Biology, Imperial College London, Hammersmith Campus, Du Cane Road, London W12 0NN,
United Kingdom. E-mail: venu.jain@imperial.ac.uk
CLINICAL OBSTETRICS AND GYNECOLOGY
Clinical Features
TTTS occurs in approximately 15% of MC
diamniotic twins, affecting approximately 1
in 1600 pregnancies overall.1 It is not known
to occur in monoamniotic twins. TTTS can
also occur within MC twin pairs in triplet
and quadruplet pregnancies. TTTS is usually diagnosed on serial ultrasound indicated
VOLUME 47
NUMBER 1
MARCH 2004
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182
routinely in MC twins albeit may rarely present with polyhydramnios, preterm labor or
preterm premature rupture of membranes
(PPROM). Sonographic features of TTTS
usually manifest between 15 and 25 weeks,
although early 3rd trimester presentations
still occur. The net donor develops features
of anemia/hypovolemia including oliguria,
oligohydramnios, growth restriction, abnormal umbilical artery Dopplers and circulatory redistribution (Fig. 1). Anhydramnios
in the donor amniotic sac can lead to the
sonographic appearance of a stuck twin.
In contrast, the net recipient shows signs of
hypervolemia, including polyuria, polyhydramnios, visceromegaly, abnormal venous
Dopplers, cardiac enlargement/failure, and,
in extreme cases, hydrops (Fig. 1).
Before ultrasound, TTTS was diagnosed
in MC pregnancies based on growth discordance of 20% associated with a discordant fetal/neonatal hemoglobin of 5 g/dl.
However these diagnostic criteria are often
satisfied by discordant growth restriction
and are now considered unreliable for
TTTS. Paired fetal blood sampling has
shown hemoglobin discordance of 5 g/dl
in only 25% of 36 cases of TTTS, with a
mean hemoglobin difference of 3.6 g/dl.2
Discordant fetal growth (birth weight difference 20%) occurs as commonly in dichorionic as in MC twins.3
TTTS is now defined as presentation in
the mid-trimester with the oligopolyhydramnios sequence, the deepest vertical pool in the donor being 2 cm and in
the recipient 8 cm. Other supportive features are a small or non-visible bladder and
abnormal umbilical artery Doppler (absent
or reversed end-diastolic frequencies
[AEDF/REDF]) in the donor in association
with a large bladder, cardiac hypertrophy,
abnormal umbilical vein/ductus venosus
Dopplers and hydrops in the recipient (Fig.
1). Discordant intrauterine growth restriction (IUGR) can mimic the donors phenotype but should not be associated with the
recipients phenotypic features in the cotwin.
Pathophysiology of TTTS
ANATOMIC BASIS
TwinTwin Transfusion
183
184
transfusion, mediating a state of hypovolemia in the donor and hypervolemia in the recipient. Initial ex-vivo injection studies confirmed that TTTS placentae had more deep
than superficial anastomoses compared with
MC controls.4,7 Endoscopic studies, though
lacking histopathological confirmation,
confirm injection study evidence that the
majority of TTTS placentae show a higher
number of AVAs from donor to recipient
than in the opposite direction.11,12 Thrombosis of a previously compensatory reversedirected AVA from recipient to donor can
lead to rapid onset of TTTS in a previously
unaffected pregnancy.12 Notwithstanding
an endoscopic report of TTTS with no deep
anastomoses,13 ex-vivo studies show that
AVAs are present in all TTTS placentae as
opposed to 84% of controls.8 In addition,
78% pregnancies with one or more AVAs in
the absence of AAAs develop TTTS.8 The
largest ex-vivo placental injection study has
shown that AAAs are less frequent in TTTS
(24% versus 84% in controls) whereas the
frequency of AVAs and the rarer VVAs is
similar.14 In support of this, computer modeling has shown that unidirectional, or more
likely, asymmetrical bidirectional intertwin
transfusion results in hemodynamic, osmotic and physiological changes consistent
with the clinical features of TTTS.15,16
AAAs have a greater potential for hemodynamic counter balancing than VVAs by
virtue of their higher pressure differential.
TwinTwin Transfusion
growth restriction, redistribution of blood
flow, decreased renal perfusion and oligohydramnios. In advanced disease, increasing fetoplacental resistance manifests as
AEDF or REDF. In the donor kidney, degenerative changes and decreased mass of
the renal tubules may progress to renal tubular dysgenesis.23 Decreased glomerular filtration and renal perfusion in the donor may
be responsible for a renal defect which is
more likely a primary developmental defect rather than secondary to ischemia.23
Apoptosis-mediated loss of proximal and
medullary tubules is thought to be a precursor of more diffuse renal tubular atophy.24
In the recipient, phenotypic features have
largely been attributed to hypervolemia.
High atrial natriuretic peptide (ANP), secreted in response to fluid overload, along
with concomitant suppression of antidiuretic hormone (ADH) mediates the associated polyuria and polyhydramnios. 25
Amniotic pressure is raised in the polyhydramniotic sac and its amelioration by amnioreduction is associated with increased
uterine artery blood flow and improved fetal
acidbase status.2628 Hypervolemia also elevates cardiac preload. Findings of hypertension in the recipient indicate that elevated
afterload may also contribute to cardiovascular dysfunction.29 Implicated in this is endothelin, levels of which are raised in the recipient compared with the donor.30 Cardiac
failure is evident initially by venous Doppler
changes including AEDF/REDF in the ductus venosus, pulsatile flow in the umbilical
vein and tricuspid regurgitation, and later by
fetal hydrops (Fig. 1). Cardiac hypertrophy
secondary to raised afterload sometimes results in a functional right ventricular outflow
obstruction.31,32 Recipient kidneys are enlarged, congested and show hemorrhagic infarction, with glomerular and arterial
changes resembling polycythemia and hypertension.33
Disturbances of the renin-angiotensinaldosterone system (RAS) have been described in the donor as well as the recipient.33,34 There is overexpression of renin in
185
Clinical Course
All MC pregnancies should be scanned every 2 to 4 weeks for early detection of
growth and amniotic fluid discordance,
Doppler abnormalities and other features of
TTTS. When minor amniotic fluid discordance is noted, scans should be done more
frequently. Fetal echocardiography is indicated in all MC twins in view of an increased
incidence of cardiac anomalies, (3.8% v
0.6% in singletons).32
Retrospective studies show that the median gestational age at diagnosis of TTTS is
around 21 weeks and 29 weeks at delivery.35,36 Preterm labor or PPROM occur
secondary to raised amniotic pressure with
polyhydramnios, but may also be a consequence of therapeutic procedures.37 Preterm
labor or PPROM is managed in the usual
fashion, and preterm delivery is associated
with the usual complications of prematurity.
However, preterm TTTS babies, especially
28 weeks, do much worse neonatally than
their singleton or non-TTTS twin counterparts. Cardiac dysfunction in the recipient is
186
Prediction of TTTS
Twins presenting with severe TTTS in the
mid-trimester may have hemodynamic imbalance from the first trimester manifest as
discordant increased nuchal transluscency
(NT) at 10 to 14 weeks.10,50 This is of relevance as NT is the primary screening test
for aneuploidy in multiple pregnancies. Sebire et al found that 32% of MC pregnancies
with increased NT subsequently developed
TTTS (likelihood ratio 3.5, 95% CI 1.96.2)
although only 28% of cases were predicted.50
Another finding associated with later
TTTS is folding of the intertwin membrane
at 1517 weeks. This is seen in 32% of MC
pregnancies, 43% of which subsequently
develop TTTS (likelihood ratio 4.2, 95% CI
3.06.0).50 However the utility of this subjective finding in predicting TTTS that remains debatable.
Doppler studies of placental anastomoses
have shown that TTTS develops in 15% of
patients with an AAA versus 61% without
an AAA (OR 8.6).14 Conversely however,
25%30% of TTTS placentae still have an
AAA, although, when TTTS develops in
the presence of AAAs, it is associated with
considerably higher perinatal survival.14
AAAs can be detected after 18 weeks using spectral and color Doppler with an 85%
sensitivity and 97% specificity, though
detection as early as 11 weeks is possible.14
Typically, the presence of an AAA is
revealed by a bidirectional speckled pattern on color or power Doppler (Fig. 3, panel
A).14,18 In a series of 105 patients with MC
pregnancies, 68 (65%) had an AAA confirmed by ex-vivo injection studies, 59
(56%) of which were identified in vivo by
Doppler.14 Computer modeling supports
varying bidirectional flow in the AAA,
the periodicity of which has been shown
to be a function of the difference in twins
heart rates (Fig. 3, panel B). 15 Further,
this bidirectional pattern transforms to
unidirectional flow in the event of intrauter-
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187
Staging
Quintero et al developed an intuitive staging
system to categorize disease severity. 53
Stages I to V are based on progressivelyworsening clinical features: stage I,
oligo/polyhydramnios sequence only with
bladder visualized in the donor twin; stage
II, bladder not visualized in donor; stage III,
critically abnormal Dopplers (AEDF or
REDF in the donor umbilical artery, or reverse flow in the ductus venosus or pulsatile
flow in the umbilical vein in the recipient);
stage IV, hydrops in recipient; stage V, demise of one or both twins (Fig.1). This staging system for TTTS was designed to assist
with determination of prognosis, and to
standardize comparison of treatment results.53,54 However, attempts to validate
staging by outcome may be distorted by the
treatment paradox ie, improving outcomes
188
Complications
In addition to the morbidity associated with
TTTS discussed above, some problems
merit further discussion.
NEUROLOGICAL COMPLICATIONS
TwinTwin Transfusion
megaly, subependymal pseudocysts, small
white matter cysts and basal ganglia echogenicity or lenticulostriate vasculopathy.36,61
Antenatally-acquired lesions should be differentiated from postnatally acquired ones
which include hemorrhages and PVL evident on delayed neonatal imaging.63 Surprisingly, in the absence of TTTS, 23% of
MC twin survivors also have abnormal postnatal ultrasound findings.62 In addition,
postnatal ultrasound studies in term infants
show an incidence of minor lesions as high
as 27%30%.64,65 However, none of these
infants had cerebral palsy or major developmental delay.64,65 The varying incidence of
ultrasound abnormalities in TTTS affected
survivors and control term infants in various
studies is also likely to be influenced by the
sensitivity of the imaging technique used in
different studies.
CARDIOVASCULAR COMPLICATIONS
Although MC twins have a six-fold increased risk of congenital cardiac anomalies, this is even higher in TTTS (6.9% with
versus 2.3% MC twins without TTTS).32
TTTS survivors are at increased risk of both
congenital and acquired cardiovascular lesions.31,32 All recipients manifest variable
degrees of biventricular hypertrophy and dilation, with tricuspid regurgitation and decreased ventricular function, while no specific acquired cardiac dysfunction occurs in
donors either in utero or after birth.29,31,32,66,67
Volume overloading and systemic hypertension in the recipient cause myocardial
hypertrophy.29 This hypertrophic cardiomyopathy can cause subvalvular stenosis resulting in right ventricular outflow tract obstruction necessitating valvotomy in infancy
in some cases.31,32 Though biventricular hypertrophy is frequent in recipients, an acquired right outflow tract anomaly has been
described in absence of systemic hypertension.68 Cardiac hypertrophy is associated
with subsequent cerebral palsy, although
this may simply be a function of disease
severity.60 Although 45% to 50% of recipients exhibit abnormal cardiac function in
189
Management
The range of therapeutic options includes
expectant management, serial amnioreduction, septostomy, laser photocoagulation of
placental shunts, and selective feticide. Because of the high untreated perinatal mortality and morbidity, expectant management
will only be appropriate in a few mild cases.
MEDICAL THERAPY
190
Serial amnioreduction to normalize amniotic fluid volume is the earliest and arguably
the simplest and most accessible of the various treatments advocated in TTTS.37 The
most obvious mechanism by which amnioreduction works is decreased fluid volume
reducing the risk of preterm labor and
PPROM.72 Patients with polyhydramnios
have raised amniotic pressure and its reduction is associated with improvement in fetal
status.27 Polyhydramnios is associated with
impaired uteroplacental perfusion as suggested by an inverse correlation between the
degree of hydramnios and impairment in fetal blood gases.73 Amnioreduction leads to a
74% increase in uterine arterial flow, which
suggests a further mechanism for the beneficial effects of amnioreduction.26 PPROM in
TTTS may paradoxically improve outcome
by a similar mechanism.
Amniocentesis is indicated when amniotic fluid index (AFI) is >40 cm or the deepest vertical pool >12 cm, the threshold for
increased amniotic pressure. Each liter of
fluid reduces AFI by about 10 cm. Previously, the goal was to lower the AFI to <25
cm,37 but increasingly, targets of <15 or <10
cm are used in an attempt to prolong the interval between procedures.74 Procedurerelated risks include PPROM (approximately 6%), chorioamnionitis and placental
abruption though the incidence is low.37,43
In a retrospective analysis, in cases with severe TTTS before 28 weeks gestation, serial
amnioreduction led to an improvement in
perinatal survival to 60% (versus <20%
without treatment), which included a 50%
double and 20% single survival.1 However,
TwinTwin Transfusion
reported benefit was a decrease in need for
repeat procedures with septostomy (40%
versus 70% with amnioreduction). In terms
of technique, Nd:YAG laser can be used as
an alternative to needling to create the defect
in the intertwin membrane, though without
any significant advantages.75 The procedure
has at least a theoretical risk of intertwin
cord entanglement through extension of the
defect in the dividing membrane, though the
hole created is usually small (microseptostomy).
Despite its ameliorative effects, it is again
difficult to see how septostomy addresses
the underlying transfusional basis of the disease. In this light, computer modeling has
shown that merging of the two amniotic
compartments to allow swallowing of the redistributed fluid by the donor has minimal
effect on donor blood volume or growth.80,81
LASER ABLATION
Laser ablation is the only treatment that addresses the primary basis of the disease; cessation of intertwin transfusion. Laser ablation entails photocoagulation of anastomotic
vessels between the two chorionic circulations under direct vision. Typically, an endoscope is introduced transabdominally into
the uterine cavity under ultrasound guidance
and Nd:YAG laser applied via a 400600
m optic fiber introduced thorough the side
channel.82,83
Non-Selective Laser Ablation
In this initial technique, all vessels approaching or crossing the membrane between the twins were ablated.84 However,
this approach met with limited success.
Ville et al carried out laser ablation of placental anastomoses in a series of 132 patients with severe TTTS at a median gestational age of 21 weeks. Overall fetal survival
was 55%, and the number of pregnancies
with at least 1 survivor was 73%.58 De Lia
reported a 69% overall survival and 82% of
pregnancies had at least 1 survivor in a series
of 74 patients, though 7 patients were excluded from analysis due to pre- or intraop-
191
192
TwinTwin Transfusion
months to 3 years showed a 9% incidence of
cerebral palsy.93 Considering all the data, it
appears that the incidence of cerebral palsy
with non-selective and selective laser is
comparable to the overall incidence of cerebral palsy in TTTS (8%) and argues against
an obvious improvement in neurologic outcome with laser therapy. However, Sutcliffe
et al found no cases of cerebral palsy in
single survivors following non-selective laser treatment, suggesting that non-selective
laser may result in single intrauterine death,
the resultant functionally dichorionic placentae protect against agonal transfusional
sequelae.93 An alternative explanation could
be that this treatment modality improves
overall survival merely by salvaging fetuses
that have already suffered a neurologic insult.
SELECTIVE FETICIDE
193
194
fetus and the uterine wall. Serial applications of coagulation lasting 60 seconds are
used with incremental power as needed (20
to 50 W) until the bubbling stops. Cessation
of blood flow is confirmed by color Doppler.
Advantages include use of a single port, a
high success rate in achieving cord occlusion, a shorter procedure duration, a 76% to
93% survival of the remaining twin, and a
lower albeit substantial (12% to 20%) incidence of PPROM.94,103,104 An important
aspect of this treatment is the varying legal
status of termination of pregnancy after viability. This option may be feasible after 24
weeks in jurisdictions such as the United
Kingdom, France and Israel but is not
widely available in other countries including
most of the United States.
A novel recently developed interstitial laser procedure is useful for selective termination in the early mid trimester (<16 to 17
weeks).105 This technique involves introducing a 20 gauge needle into the abdomen
of the selected twin close to the vitelline arteries and intrahepatic vein under ultrasound
guidance.105 Then a 400 mm to 600 mm la-
TwinTwin Transfusion
ents to countenance termination of a structurally normal fetus, along with the natural
tendency of clinicians to delay such a procedure until it becomes absolutely necessary,
which obviously can result in an unexpected
fetal loss.
MANAGEMENT OF SINGLE
INTRAUTERINE DEATH
195
DELIVERY
196
(95% CI 1.28.3), P = 0.02). Thus, the number needed to treat (NNT) for amnioreduction versus laser in early stage disease indicated an extra double survival for every four
or five cases treated by amnioreduction
compared with laser. Since some cases with
AR will progress, if this analysis had been
done for worst rather than initial stage, the
survival advantage in early disease may be
even greater in favor of amnioreduction.
Analysis of another useful parameter to assess pregnancy outcome, any (or at least
one) survival rate, was higher for laser in
stage III and IV (82% versus 45% for amnioreduction, OR 2.8 (95% CI 1.716.7), P
< 0.01). Thus, in advanced disease, the NNT
for laser versus amnioreduction indicated
that every third patient treated with laser resulted in an extra pregnancy with at least 1
survivor. In conclusion, serial amnioreduction and/or septostomy is associated with
better outcomes in stage I or II disease, while
selective laser ablation is associated with
better outcomes in advanced disease (stage
III/IV).
FIGURE 5. Categorical reanalysis of survival data from twin-twin transfusion syndrome (TTTS)-affected pregnancies treated with amnioreduction
or selective laser (Quintero et al, Am J Obstet Gynecol 2003;188:1333
1340). Panel A: Perinatal (overall), double (both twins) and any (at least one)
survival rates in mild (combined stage I and II) TTTS. Panel B: Survival
rates in severe (combined stage III and IV) TTTS. *versus amnioreduction,
P < 0.05.
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Our suggested sub-categorization of
Quintero stage, in which the presence or absence of an antenatally-detected AAA is denoted a and b respectively, not only allows identification of good from bad prognosis cases within each stage, but also an
AAA-positive subgroup within Stage III
(IIIa) which is associated with better perinatal and double survival than AAA-negative
Stage I and II (Ib and IIb) cases.49 Incorporation of AAA into a modified TTTS staging
system should improve prediction of perinatal survival, and may facilitate treatment selection to optimize outcome. Stages Ia, IIa
and IIIa form a group with good survival
prognosis, which can be managed conservatively or with temporizing measures such as
amnioreduction and/or septostomy, and
then delivered electively by 32 to 34 weeks.
Stages Ib and IIb comprise a group with intermediate survival prognosis. While amnioreduction is associated with better perinatal survival than laser ablation for Stage
III,54 some of this group nevertheless progress to more advanced stage disease, eventually requiring definitive treatment. Stages
IIIb and IV form the group with the poorest
survival, in which more invasive albeit definitive treatment such as selective laser or
cord occlusion appear indicated. Selective
laser ablation of anastomotic vessels has
been shown to result in higher perinatal,
double and any survival rates than amniocentesis procedures for stage IV disease,54
while cord occlusion in Stage III/IV disease
is associated with empirically higher survival than amnioreduction.94
Notwithstanding this, there are some arguments against a stage based approach to
treatment. Firstly, little information is available on neurologic sequelae by stage, and future studies will now be needed to stratify by
modified stage. Next a proportion of patients with early stage disease will progress
to require more definitive treatment, and
membranous detachment after septostomy
or intra-amniotic bleeding after amnioreduction may render laser technically difficult, reducing the chances of success. Fi-
197
Conclusion
TTTS is a common disease process affecting
monochorionic diamniotic pregnancies.
Though the pathophysiology is poorly understood, interplacental anastomoses and
unbalanced intertwin transfusion form the
etiologic basis. Several therapeutic options
are available including amnioreduction,
septostomy, laser ablation of vascular anastomoses, and selective feticide. With these
modern treatment modalities, overall perinatal survival rates have improved from
20% to around 60% to 70%. However, the
majority of affected pregnancies will still
lose at least one baby, with significant long
term neurologic morbidity in about 10% of
the survivors. Thus, outcomes, though substantially improved by intervention, remain
suboptimal, partly due to poor understanding of the underlying pathophysiology and
partly because of poor case selection for intervention. Current evidence supports a
stage-based approach to treatment, with a
further survival advantage conferred by the
presence of an AAA. Conservative treatment such as amnioreduction and septostomy are favored for early stage disease. In
advanced disease, with a <50% probability
of survival of one or both twins, selective
laser or cord ligation confer better outcomes.
With all treatment modalities, timely intervention in a tertiary referral center that routinely undertakes these procedures is essential.
Acknowledgments
We acknowledge programme funding for
our work on twintwin transfusion syndrome from the Richard and Jack Wiseman
Trust.
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