Seminars in Fetal & Neonatal Medicine 15 (2010) 15–20

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Seminars in Fetal & Neonatal Medicine

journal homepage: www.elsevier.com/locate/siny

Twin-to-twin transfusion syndrome: current understanding of pathophysiology,

in-utero therapy and impact for future development
Michael Bebbington a, b, *
a
Center for Fetal Diagnosis and Treatment, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
b
University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA

s u m m a r y

Keywords: Whereas monochorionic twins account for only 30% of twin gestations, they contribute to a dispropor-
Fetal cardiology tionate extent to the overall twin perinatal morbidity and mortality. Twin-to-twin transfusion syndrome
Fetal therapy can occur at any point in a monochorionic gestation but is associated with significant increases in both
Laser therapy
morbidity and mortality when it develops before 26 weeks of gestation. It is still not possible to predict
Monochorionic twins
accurately those pregnancies that will be affected. This has resulted in the practice of routine ultrasound
Twin-to-twin transfusion syndrome
surveillance beginning at the end of the first trimester. Our understanding of the physiology still has
many gaps but there is an increased recognition of the heterogeneity that exists especially in the early
stages of the disease. The role of the cardiovascular response of the recipient twin offers the potential for
further refining the application of our current treatment modalities and may offer insight into future
therapies. The optimal therapy at this point in time resides clearly with selective laser photocoagulation,
and further refinements of techniques and patient selection may continue to improve outcomes. Finally,
the in-utero responses generated by the fetuses to the physiologic stress of twin-to-twin transfusion may
influence their response or ability to respond to cardiovascular stress in later life. If there is in-utero
programming, then the detection and timely treatment of conditions such as twin–twin transfusion
syndrome may have lifelong implications for both members of the twin pair.
Ó 2009 Elsevier Ltd. All rights reserved.

1. Introduction postimplantation blastocyst phase then monochorionic mono-

Monozygotic (MZ) twin pregnancies account for about 30% of
spontaneously conceived twins. It is estimated that the occurrence
of MZ twins is 0.4–0.45% of non-stimulated in-vivo conceptions.1
The incidence of monochorionic twins is rising, owing to the
increase in the use of assisted reproductive technology (ART)
to achieve pregnancy. The use of ART has been associated with
a 2–12-fold increase in the conception of MZ twins.2 This is
important because of the increased perinatal risk in twin gestations
in general but in MZ twins in particular.
In all, 25–30% of MZ twins are dichorionic, diamniotic (DCDA)
meaning that the embryo splits before embryonic cell differentia-
tion. The perinatal outcome of dizygotic (DZ) twins and dichorionic
MZ twins does not differ: 70–75% are monochorionic diamniotic
(MCDA) where the inner cell mass divides during the preimplan-
tation blastocyst stage. If the division takes place in the
* Center for Fetal Diagnosis and Treatment, Children’s Hospital of Philadelphia,
34th Street & Civic Center Blvd, Philadelphia, PA 19104, USA. Tel.: þ1 267 426 7187;
fax: þ1 215 590 2447.
E-mail address: bebbington@email.chop.edu
amniotic (MCMA) twins occur. Only 1–2% of MZ twins are MCMA. It
is the monochorionic twins that are susceptible to additional
complications because of their unique placental architecture. Both
fetuses share the placental mass and virtually all monochorionic
twin pregnancies have vascular anastomoses that allow the flow of
blood between the fetuses. Normally this flow is balanced with
equal amounts exchanged between the two fetuses. In about 15% of
cases, the flow becomes unbalanced and this creates the environ-
ment for the development of twin-to-twin transfusion syndrome
(TTTS). Left untreated, the perinatal mortality rate is about 90%.3
2. Pathophysiology
TTTS is not a homogeneous clinical entity and encompasses
a spectrum of severities. It can develop at different gestational ages
and with different degrees of clinical findings. There can be
a dynamic nature to the findings from one evaluation to the next.
Some cases demonstrate rapid progression whereas others follow
a more indolent course. It is difficult to completely understand the
reasons for the degree of clinical variations that are observed and at
present it is not possible to predict whether a patient will display
a stable type of TTTS or show rapid clinical progression.

1744-165X/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.siny.2009.05.001
16 M. Bebbington / Seminars in Fetal & Neonatal Medicine 15 (2010) 15–20
Commonly MC placentas have anastomoses between pairs of
arteries (AA) from the different circulations and less commonly
between pairs of veins (VV). These AA and VV anastomoses lie on
the surface of the placenta and mediate bidirectional flow with the
net direction and volume of flow varying according to the pressure
dynamics between the circulations of the two fetuses. The unbal-
anced transfusion of blood is mediated at least in part by arterio-
venous (AV) anastomoses within the placenta. The number and size
vary within each placenta but each only allows for unidirectional
flow. The presence of AV anastomoses without a compensating AA
anastomosis is associated with a higher risk for the development of
TTTS.4 This underlying angio-architecture is likely further influ-
enced by the diameter of the vessels involved and the intrinsic
placental resistance.
If the shift of blood flow becomes significant, the donor twin
becomes hypovolemic and oliguric while the recipient twin
becomes hypervolemic and polyuric. In the donor twin, the renal
system, in response to the decreased circulating volume, activates
the renin–angiotensin system (RAS). The effect is to increase tubular
reabsorption and the production of angiotensin 2, mediating vaso-
constriction to maintain circulating volume. This produces hyper-
tension within the donor. This may also have the paradoxical effect
of decreasing renal and placental perfusion, further worsening oli-
guria and resulting in growth restriction. The observation of
decreased or absent diastolic flow in the umbilical artery of the
donor would implicate the effect of these endocrine products on the
vascular tone of the placental bed. In the recipient twin, a variety of
mediators may be involved in response to increased blood volume.
The increased atrial pressure mediates an increase in cardiac atrial
natriuretic peptide synthesis. This increases glomerular filtration
rate and decreases tubular reabsorption in the kidney.5 Suppression
of antidiuretic hormone also increases the recipient’s production of
urine. Renal downregulation of the RAS is the expected response to
the recipient hypervolemia, and study of the recipient kidneys has
revealed changes consistent with a hypertensive microangiopathy
due to high levels of circulating RAS effectors.6 It has been
hypothesized that these effectors are transferred from the donor to
the recipient through the placental anastomoses. A recent study has
shown that the recipient placenta may play a role in the source for
RAS activation in the recipient twin.7 Cardiovascular findings in the
recipient twin such as ventricular hypertrophy, atrioventricular
(AV) valve regurgitation and increased pulmonary outflow and
aortic outflow velocities can be attributed to volume overload. Other
findings, however, are inconsistent with this simple perspective. If
the changes within the recipient only occur in response to volume
loading then there should be an increase in the combined cardiac
output. This has not been observed. The observed cardiomegaly
appears to result primarily from myocardial hypertrophy rather
than cardiac dilation.8 The development of pulmonic stenosis and
obstruction of the right ventricular outflow tract would not be
expected strictly on the basis of volume loading. These findings
suggest an increase in cardiac afterload secondary to the develop-
ment of systemic hypertension.9 Endothelin-1, a potent vasocon-
strictor, has been implicated in the production of systemic
hypertension in the recipient twin.10
Thus the imbalance of blood volume brought about by the
presence of vascular anastomoses initiates a cascade of events in
both fetuses that would be somewhat adaptive were they not
confined to an intrauterine environment but instead lead to signif-
icant morbidity and mortality that is associated with untreated TTTS.
3. Clinical diagnosis
There is a spectrum of sonographic features that may suggest
the diagnosis of TTTS. There must be evidence of monochorionicity
that includes the presence of a single placenta, a thin inter-twin
membrane usually measuring a thickness of <2 mm, and the
absence of a twin peak sign. In any twin gestation, the establish-
ment of chorionicity is paramount at the time of the earliest
ultrasound evaluation. TTTS is defined sonographically by
discrepancy in the amount of amniotic fluid. There must be poly-
hydramnios with a deepest vertical pocket of >8 cm in the sac of
the recipient twin, and oligohydramnios with a deepest vertical
pocket of <2 cm in the sac of the donor twin. In some European
centers the gestational age is taken into consideration with poly-
hydramnios consisting of a deepest vertical pocket of >8 cm before
20 weeks of gestation and >10 cm after 20 weeks. Other sono-
graphic features include a discordance in sizes between the co-
twins of >20%, concordant fetal gender, Doppler changes within
the fetal vasculature, frank hydrops or demise of one or both
fetuses. Current clinical staging follows that proposed by Quintero
(Table 1).11 This staging system has been a very useful construct to
allow for comparison of treatment results and for choosing
between various management strategies as it incorporates the
severity of the underlying disease. It does, however, create the
impression that the natural history of TTTS follows an orderly
progression over time. Clinical experience has shown that this is
not the case. The natural history of TTTS is variable and unpre-
dictable. This staging system also does not incorporate elements
describing the fundamental cardiovascular perturbations that are
central to understanding of the disease and that are present in
subtle form even at the earliest stage of the disease process. Rychik
et al. have proposed the addition of a cardiovascular scoring system
from the Children’s Hospital of Philadelphia (CHOP) to quantify the
magnitude of cardiovascular derangement (Table 2).12 A more
precise gradation of severity based in the physiologic underpin-
nings of the disease should augment and refine the clinical diag-
nosis and assist in the measuring of the effectiveness of various
treatment modalities or possibly assist in the selection of patients
for specific treatments. Significant degrees of cardiovascular
abnormalities are seen even in the early Quintero staging such that
a substantial number of twin pairs had a higher grade of disease
severity based on the cardiovascular assessment than that desig-
nated by the Quintero stage.
Various attempts have been made to identify sonographic
features that may predict or increase the likelihood of developing
TTTS. The first has been the use of nuchal translucency (NT)
measurements done between 11 and 13þ6 weeks of gestation.
Increased NT is a marker for chromosomal anomalies, cardiac
defects and a range of genetic syndromes. It has also been postu-
lated that the underlying hemodynamic changes in TTTS may be
present much earlier than is apparent from our current sono-
graphic criteria and may manifest as increased NT in the recipient
fetus. One study evaluated the presence of an NT measurement
>95th percentile for gestational age in MCDA twins that were
structurally and chromosomally normal. The definition of severe
TTTS included cases with an ultrasound diagnosis consistent with
Table 1
Staging of twin-to-twin transfusion syndrome.
Stage Findings
1 Polyhydramnios in recipient sac (MVP >8 cm) and oligohydramnios in the
donor sac (MVP <2 cm)
2 No visible bladder in the donor twin
3 Doppler abnormality consisting of absent or reverse flow in the umbilical
artery, reverse flow in the ductus venosus or pulsatile flow in the umbilical
vein
4 Ascites or hydrops in either fetus
5 Demise of either fetus
MVP, maximum vertical pocket of amniotic fluid.
 M. Bebbington / Seminars in Fetal & Neonatal Medicine 15 (2010) 15–20
Table 2
Children’s Hospital of Philadelphia (CHOP) Cardiovascular Score.
Recipient twin
Ventricular characteristics Dilatation
Hypertrophy
Systolic dysfunction
Valve function Tricuspid regurgitation
Mitral regurgitation
Venous Doppler characteristics Tricuspid inflow
Mitral inflow
Ductus venosus flow
Umbilical vein flow
Great vessel analysis PA vs Ao size
Donor twin UA Doppler
PA, pulmonary artery; Ao, aorta; AEDF, absent end diastolic flow; REDF, reverse end diastolic flow; UA, umbilical artery.
Quintero stage 2 that resulted in pregnancy loss, intrauterine fetal
demise (IUFD), intrauterine treatment or postmortem evidence
that the cause of death was TTTS. The presence of an increased NT
in at least one of the fetuses predicted the development of severe
TTTS with a sensitivity of 0.32, a specificity of 0.88 and a positive
likelihood ratio of 1.45.13 Kagan et al. evaluated the ability of
discordance in the measurement of NT between 11 to 13þ6 weeks to
predict the subsequent need for endoscopic treatment of TTTS.14 A
discordance of more than 20% was associated with a sensitivity of
0.57, a specificity of 0.77 and a positive likelihood ratio of 1.73. As
a screening tool, the use of discordant NT measurements does not
provide sufficient discrimination to be recommended for routine
use. Combining increased NT thickness with abnormal flow in the
ductus venosus (DV) has also been proposed as a screening tool for
early TTTS. An abnormal NT thickness was defined as >95th
percentile for gestational age with a discrepancy between the
co-twins of 0.5 mm considered significant. An abnormal DV
waveform was defined as reversal of the A-wave during atrial
contraction. In a prospective series of 50 cases, four cases developed
TTTS.15 An abnormal DV Doppler was seen in all four cases. An
additional two cases with abnormal DV Doppler developed another
complication. None of the remaining 44 cases with a normal DV
Doppler developed TTTS. This results in a sensitivity of 0.66 and
a specificity of 1.0.
Folding of the inter-twin membrane is an ultrasound marker
that demonstrates a decrease in the amount of amniotic fluid in one
sac compared to the other and has also been proposed as
a screening test for MCDA twin gestations that will develop TTTS.
Sebire et al. prospectively evaluated 83 MCDA pregnancies that
presented for routine NT screening.16 Serial ultrasound evaluations
were performed at 10–14, 15–17 and 19–21 weeks. Membrane
folding was seen in 23 cases, 12 of which developed severe TTTS.
The remaining 11 had a more ‘moderate’ syndrome with a subjec-
tive major discrepancy in the amniotic fluid volume between the
two sacs. Thus 52% of those observed to have membrane folding
developed severe TTTS. Only one of these was detected at the time
of the initial ultrasound done at 10–14 weeks. Although this
appears to be a useful marker, what is unclear is whether this
provides additional information over the simple observation of
discordance in the amniotic fluid volume during a routine ultra-
sound. A subsequent evaluation done by the same group showed
a sensitivity of 0.43, a specificity of 0.98 and a positive likelihood
ratio of 21.5.13
The presence of AA anastomoses is considered protective for the
development of TTTS. Placental mapping for the presence of AA
anastomoses by color flow and spectral Doppler has technical
limitations, the majority of anastomoses being detectable only after
18 weeks of gestation.17 Increasing gestational age, the presence of
an anterior placenta and larger diameter vessels enhanced the
ability to detect an AA anastomosis. The overall sensitivity and
17
0 1 2 3
None Mild >Mild
None Mild >Mild
None Mild >Mild
None Mild >Mild
None Mild >Mild
2 peaks 1 peak
2 peaks 1 peak
Forward Notching Reversal
No pulsation Pulsation
PA > Ao PA ¼ Ao PA < Ao
Normal Decrease AEDF REDF
specificity measured 0.85 and 0.97 respectively. The odds ratio of
developing TTTS if an AA anastomosis was not detected was 8.6.
This demonstrates feasibility of detection; nevertheless, if they are
not detected, is it that they are truly not present or does detection
require a certain level of special skill or patience during the eval-
uation? Factors relying on a special level of skill or persistence will
never perform as well in general use as they do with those that
originate them.
Again as a screening tool, it is unclear whether any of these
provides additional benefit over the observation of a discrepancy in
the amniotic fluid volumes. A study of multifactorial screening
confirms this impression.18 Evaluating a group of 202 MCDA
pregnancies with multivariate regression, the only factors that
significantly predicted an adverse outcome, including TTTS, were
differences in the crown–rump length and discordance in the
amniotic fluid volume in the first trimester. Screening strategies
may be able to identify a subgroup of patients at higher risk, but it is
unclear whether those cases identified at a lower risk will be
subjected to different clinical care following their risk stratification.
The fact that none of the above sonographic screening tools
functions well individually or collectively underscores that the best
method for early diagnosis is likely the regular ultrasound evalua-
tion of ‘at risk’ monochorionic pregnancies. This strategy too is not
presently supported by strong research findings. A small case series
evaluated the ability to make a timely diagnosis of TTTS with
a program of biweekly ultrasound combined with patient reporting
of symptoms suggestive of TTTS.19 Although only four of 23 patients
developed TTTS, the authors concluded that sonography combined
with maternal symptom monitoring allowed the diagnosis and
management of all cases before the onset of severe complications.
4. Treatment
Since the publication of the Eurofetus randomized trial
comparing amnioreduction with selective laser photocoagulation,
there has been no question that laser therapy is currently the
optimal therapy for TTTS that develops before 26 weeks of gesta-
tion.20 Of all the available therapies, it is the one that seeks to
interrupt the vascular connections on the chorionic plate that are
responsible for the development of the syndrome. The group that
underwent laser therapy had a significantly higher mean gesta-
tional age at delivery (33 vs 29 weeks) along with higher survival of
at least one fetus to 28 days of age (76% vs 56%). Postnatal follow-up
was only to 6 months’ duration but demonstrated improved
neurologic outcomes with decreased risk of periventricular leuko-
malacia in the laser group (6% vs 14%) and a higher likelihood of
being free of neurologic complications at 6 months of age (52% vs
31%). The Eurofetus trial confirmed the many prior studies of lesser
epidemiologic rigor. A recent meta-analysis of ten of these studies
supported the superiority of laser therapy over amnioreduction.21
18 M. Bebbington / Seminars in Fetal & Neonatal Medicine 15 (2010) 15–20
The technique for laser therapy has undergone some changes
since it was first proposed by De Lia.22 A laparotomy is no longer
performed with the procedure now performed percutaneously. The
use of general anaethesia has given way to the use of conscious
sedation or local anaesthetic. The method for ablation of the vessels
crossing the inter-twin membrane has changed from a non-
selective approach, in which all vessels crossing the inter-twin
membrane were photocoagulated,23 to a selective approach
involving precise identification of the anastomotic vessels.24 This
change resulted in an improved survival of at least one fetus from
61% in the non-selective group to 83.1% in the selected group
largely as a result of less dual intrauterine demise in the selected
laser group.
Further refinements in laser technique have been explored.
Quintero et al. have proposed a sequential selective laser photo-
coagulation of the communicating vessels.25 The rationale for
photocoagulation of the AV anastomoses from the donor to the
recipient first is that this could improve the hemodynamic status of
the donor and result in less demise of the donor twin. Although
they do report a lower rate of IUFD among donors in the sequential
technique (21.4% vs 7.3%), this was a non-randomized study and the
groups were severely unbalanced in terms of size. Also, there was
no difference between the groups in overall stage – the sequential
group had twice as many stage 1 patients as did the selective group.
Adoption of this technique awaits further evaluation.
The finding of residual anastomoses following laser surgery is of
great clinical concern. Depending on the number, size, direction
and vessels involved they can result in persistent TTTS, reversal of
TTTS, twin anemia polycythemia sequence (TAPS), intrauterine
demise of both twins, or hypotensive sequelae in a surviving twin.
These residual connections can represent anastomoses that were
missed at the time of laser ablation or revascularization of previ-
ously ablated vessels. In one study that evaluated 50 placentas
postpartum from MCDA twins that had undergone laser ablation,
residual surface anastomoses that should have been treated with
laser ablation were found in 32%.26 The pregnancies with residual
anastomoses were more frequently associated with adverse
outcome such as double fetal demise or evidence of anemia in one
twin requiring intrauterine transfusion. Case reports have been
published that use treatment of fetal anemia through intrauterine
transfusion to determine the rate of blood flow through the residual
AV anastomosis.27 Advanced mathematical modeling of twin-to-twin
transfusion has led to the development of equations that can be used in
similar situations.28 A more recent study found a similar frequency
of residual surface anastomoses but noted that most measure <1 mm
in diameter and are more commonly located near the placental
margins.29 The presence of deeper anastomoses within the placenta
that cannot be photocoagulated by laser therapy have also been
identified.26 Their contribution to the post-laser complication rate
from ongoing exchange of blood would appear to be unimportant
in producing hematological or hemodynamic changes of clinical
significance.30
The occurrence of demonstrated residual anastomoses has led
to several procedural changes. It is incumbent on those who
perform laser therapy to be exceedingly vigilant when mapping the
placenta. This may involve multiple runs over the vascular equator
to look for residual small anastomoses that may have been missed
initially and to ensure that all laser sites are adequately photo-
coagulated. A modification of the selective technique has been
proposed that involves performing an initial selective laser ablation
and then using the laser to connect the ablation sites. This essen-
tially photocoagulates the vascular equator in what is known as the
‘Solomon’ technique. There is currently a randomized trial
underway to determine whether application of this technique is
able to reduce the frequency of TAPS or recurrent TTTS. The second
is the recommendation for serial weekly surveillance of middle
cerebral artery Doppler velocities after laser therapy to detect
developing anemia (TAPS) that is amenable to treatment with
intrauterine transfusion or to detect signs of persistence of TTTS or
reversal of TTTS.
Amnioreduction is no longer the mainstay of therapy for TTTS. It
may, however, still have a role to play in the management of TTTS
under certain conditions. It may be a useful procedure to allow
a patient to be transported to a center where more definitive
therapy may be offered. It may be useful to decompress the uterus
in cases where there is evidence of cervical shortening or proximal
funneling to allow a cervical cerclage to be placed before laser
therapy. It can be used in managing symptomatic polyhydramnios
when TTTS develops outside of the gestational age where laser
therapy can be performed or where laser therapy is technically not
possible. Finally it may be a useful therapy in the management of
stage 1 TTTS.
Since the initial clinical staging was proposed by Quintero, it has
been realized that a number of early stage TTTS cases do not
progress and remain at stage 1 or may even regress. Several studies
have evaluated this. Taylor et al. reported a progression rate of 31%
in a cohort of 22 stage 1 patients.31 Dickinson and Evans found
a progression rate of 45.5% in their cohort of 22 patients.32 Finally in
a cohort of 46 patients with stage 1 disease, O’Donoghue et al.
found a 30.4% rate of progression.33 Our own study of 42 patients
with stage 1 TTTS revealed a progression rate of only 10%.34 Though
studies have found that amnioreduction did not alter the rate of
progression or regression, it can still be useful for symptomatic
relief from polyhydramnios. In a similar way, selective termination
of one fetus by bipolar cord coagulation or radiofrequency ablation
is only selectively used in the management of TTTS. Cases where
there are discordant anomalies, pre-existing injury or imminent
demise of one twin would be considered situations where selective
termination could be offered as a means of protecting the co-twin
from the risks of a spontaneous intrauterine demise.
The treatment of stage 1 TTTS is controversial; whether the best
therapy is simple observation, amnioreduction or laser photoco-
agulation has not yet been determined. Other therapies such as
selective termination via bipolar cord coagulation or radio-
frequency ablation or termination of the pregnancy are not usually
considered at this early stage. There are few studies that report
outcomes for laser treatment specifically for stage 1 disease. Mid-
deldorp et al. reported on the outcomes of 100 pregnancies
managed by laser surgery.35 From that series there were 10 cases of
stage 1 TTTS treated with laser with a 95% survival at birth. They do
not breakdown their postnatal mortality events by stage and so it is
impossible to determine the survival to discharge from hospital for
the subgroup of stage 1 cases. The Eurofetus trial20 included 11
pregnancies with stage 1 TTTS, six in the laser group and five in the
amnioreduction group. They reported that the survival rate was
higher in the laser group compared to the amnioreduction group
for all stages, but they only reported a comparison between the
therapies for stages 1 and 2 combined, showing 86% survival at 6
months for the laser group and 58% survival for the amnioreduction
group. As such, the results for the 11 stage 1 patients are grouped
with the results from the much larger stage 2 group of 62 patients,
so it is difficult to draw definite conclusions on outcomes in this
smaller group. If the rate of progression in stage 1 TTTS is low and
outcomes are good for those that do not progress, then is it
appropriate to expose these pregnancies to the risks of laser
therapy? In the absence of an ability to predict those cases that are
likely to progress, it is difficult to select those cases of stage 1
disease that may benefit from treatment before they progress.
There are discussions currently underway to develop a randomized
trial for the management of stage 1 TTTS.
 M. Bebbington / Seminars in Fetal & Neonatal Medicine 15 (2010) 15–20
5. Long-term outcomes
Survival of one or both fetuses is only one aspect of the
outcomes in TTTS. The mean gestational age at delivery even in
successfully treated cases is still less than that seen in MCDA twin
gestations without TTTS. Thus complications of prematurity still
factor into the long-term outcomes. The Eurofetus trial provided
information on neurologic outcomes at 6 months of age, with 52%
of surviving infants from the laser group being free of major
neurologic sequelae compared to 31% of surviving infants in the
amnioreduction group.20 Reliable assessment of neurologic
abnormalities requires a longer follow-up period than 6 months
although the occurrence of periventricular leukomalacia is a strong
predictor of the subsequent development of cerebral palsy. The
frequency of longer-term neurologic sequelae has been docu-
mented in many case series of varying size and duration of follow-
up. The largest involves 145 infants from pregnancies undergoing
laser therapy before 26 weeks of gestation.36 These infants were
followed to a mean age of just over 3 years. Children were cate-
gorized as having normal physical and neurologic development,
minor neurologic deficiency with the prospect to normalization or
severe neurologic abnormality leading to permanent disability
based on standardized testing. This showed 86.8% of children with
normal development, 7.2% with minor neurologic abnormality and
6% with major neurologic abnormality.
With the dramatic effects on cardiac physiology that are seen in
the recipient twin in TTTS, the long-term outcome of the cardio-
vascular system has also come into question. The CHOP Cardio-
vascular Score, which is a broad, multifactor representation of
cardiac function primarily in the recipient, shows a significant
reduction post laser therapy.37,38 It has also been demonstrated that
there is improvement in both the right and left ventricular
myocardial performance index post laser when compared to
preoperative assessment.39 Serial postoperative evaluations show
continued improvement over time. The development of right
ventricular tract outflow obstruction in some recipient twins is
seen to improve following laser therapy but may not resolve
completely, resulting in acquired congenital heart disease that
requires evaluation postnatally. Postnatal studies with long-term
cardiac follow-up are few. One study of 89 survivors of MCDA
pregnancies treated for TTTS with laser showed that in 87% of
survivors, postnatal echocardiography was normal at a median age
of 21.5 months.40 The prevalence of congenital heart disease and
particularly pulmonary stenosis in the recipient twin was increased
compared to the general population (11.2% vs 0.3%).
There is a need for longer-term follow-up to assess the impact of
the altered in-utero environment on the development of other
forms of cardiovascular disease.
6. Conclusions
Great strides have been made in the understanding and treat-
ment of TTTS over the last decade but much work remains. Laser
photocoagulation therapy has improved overall survival and the
rate of neurologically intact survival through prolongation of
gestation. It remains the one therapy that addresses the underlying
pathophysiology. Efforts continue to be needed to focus attention
on the risk of preterm rupture of membranes following endoscopic
treatment. This remains the Achilles’ heel of fetal therapy. There is
a need for discussions on how many treatment centers are needed
to meet the clinical demand and a means of rationalizing those
choices. Procedure related complications decrease as the number of
cases performed increases. Thus it may make sense to limit the
number of centers in order to optimize technical expertise. Further
randomized trials are needed to address clinical questions such as
19
the optimal treatment for stage 1 disease and this will require the
cooperation and participation of multiple centers. If programming
takes place within the intrauterine environment, then ongoing
long-term follow-up studies that will evaluate the children into
their school years and beyond are needed to understand the impact
of TTTS on the development of diseases in later life.
Practice points
 Monochorionic twins are associated with a dispropor-
tionately high perinatal morbidity and mortality. The
determination of chorionicity is an essential component
of any ultrasound evaluation of a twin pregnancy.
 There is no reliable way to screen MCDA twins for the
development of TTTS. Routine surveillance with ultra-
sound on a biweekly basis appears to be the most effi-
cient tool at present.
 Clinical diagnosis of even early stage TTTS should
prompt a referral to a center experienced in the evalu-
ation and management of complex MC pregnancies
including the ability to perform laser therapy.
Research directions
 Further development in the understanding of the
prenatal pathophysiology of TTTS.
 Further elucidate the long-term impact of in-utero
intervention.
 A randomized controlled trial is needed to determine the
optimal treatment for early stage TTTS.
Conflict of interest statement
None declared.
Funding sources
None.
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