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Twin-to-Twin Transfusion Syndrome: Part 1. Types and Pathogenesis

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 Twin-to-Twin Transfusion Syndrome: Part 1. Types and Pathogenesis
Ona M. Faye-Petersen and Timothy M. Crombleholme
NeoReviews 2008;9;e370-e379
DOI: 10.1542/neo.9-9-e370

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Article neonatology
Twin-to-Twin Transfusion
Syndrome: Part 1. Types and Pathogenesis
Ona M. Faye-Petersen,
MD,* Timothy M.
Crombleholme, MD†
Author Disclosure
Drs Faye-Petersen and
Crombleholme have
disclosed no financial
relationships relevant
to this article. This
commentary does not
contain a discussion
of an unapproved/
investigative use of a
commercial product/
device.
e370 NeoReviews Vol.9 No.9 September 2008
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Objectives After completing this article, readers should be able to:
1. Differentiate acute and chronic twin-to-twin transfusion syndrome (TTTS).
2. Describe the role of placental anastomoses in TTTS.
3. List the primary factors contributing to the development of TTTS.
4. Describe characteristics of the placenta in the presence of TTTS.
5. Characterize fetal adaptations to TTTS.
Abstract
Twin-to-twin transfusion syndrome (TTTS) may be acute or chronic, but chronic
TTTS complicates 10% to 20% of monochorionic twin gestations and has an 80% to
100% mortality rate if severe and left untreated. Both types are due to the presence of
placental anastomoses between the two twins, but the mechanisms involved in the
development of chronic TTTS are particularly complex and incompletely understood.
Many of the apparent pathogenic mechanisms have implications for the appearances
and cardiovascular and physiologic disturbances of neonates born following this
intrauterine condition and their response to treatment. We present an update in the
pathogenesis of TTTS that includes an overview of the placental features, fetal
adaptive and maladaptive responses, and molecular mechanisms involved in the
development of TTTS.
Introduction
Twin-to-twin transfusion syndrome (TTTS) is a gestational condition in which the
circulation of one twin and the other communicate via placental anastomoses. It is almost
exclusively restricted to monochorionic (monozygotic) twins with diamniotic monocho-
rionic (DiMo) placentations and clinically presents as two types, acute and chronic. Rarely,
TTTS can occur in dichorionic gestations but only if there is a vascular connection between
the two circulations.
Acute, clinically relevant TTTS is rare and usually occurs during delivery from a sudden
hemodynamic incident, such as cord compression or vascular rupture with vasa praevia that
affects only one of the twins. (1)(2) In these instances, the twins are of similar birthweight,
but due to peripartum acute shift(s) of blood through large, chorionic plate anastomoses,
(3) most commonly large venovenous anastomoses, (4) one twin is pale and the other is
plethoric. Initially, both twins may have similar hematocrit and hemoglobin values or the
plethoric twin has an increased erythrocyte count and hemoglobin. However, the pale twin
becomes notably anemic within hours of birth, as intravascular volume is reconstituted.
(3)(5) Acute transfusion syndrome also may occur with delivery of the first twin, with the
first twin draining blood into the second prior to clamping of the first twin’s cord.
Alternatively, following delivery and clamping of the cord of the first twin, blood may flow
rapidly from the second twin across placental anastomoses into the monochorionic
placenta due to the sudden drop in blood pressure within the placental angioarchitecture
perfused by the first twin. A similar scenario of acute transfusion can occur with intrauter-
*Associate Professor of Pathology and Obstetrics and Gynecology; Head, Microdissection Laboratory, Division of Anatomic
Pathology, The University of Alabama at Birmingham, Birmingham, Ala.
†
Director, Fetal Care Center of Cincinnati; Professor of Surgery, Pediatrics, and Obstetrics and Gynecology, University of
Cincinnati College of Medicine; Division of Pediatric General, Thoracic, and Fetal Surgery, Cincinnati Children’s Hospital
Medical Center, Cincinnati, Ohio.

ine fetal death of one twin; the placenta of the dead twin
becomes a low-resistance vascular tree, and the viable
twin may partially or quickly exsanguinate into the pla-
centa. The sudden hypotension may result in the demise
of the second twin or significant ischemic brain injury if
the co-twin survives the hypotensive episode. Finally, an
acute event can complicate chronic TTTS suddenly and
reverse the prior donor-recipient relationship. Thus, al-
though rare, acute TTTS may explain otherwise confus-
ing or paradoxic findings on antenatal ultrasonography
or at delivery. (1)(5) Careful examination of the placenta
in these clinical settings, with assessment of the presence
and types of vascular communications, can play a role in
determining the cause of unexpected neonatal hemoglo-
bin values or newborn morbidities or sudden mortality.
Chronic TTTS, hereafter designated simply as TTTS,
is a condition of a sustained, net imbalance of blood
volume transfused between twins of a DiMo placenta-
tion. Purportedly due to inter-twin vascular anastomoses
in the placenta, one twin becomes the net donor and the
co-twin becomes the effective recipient. TTTS generally
is stated to complicate 10% to 20% of all monochorionic
twin gestations, but inclusive review has revealed an
incidence of 4% to 35% in the United States. (6) The
relatively broad incidence range of TTTS likely reflects
differences in clinical criteria used to make the diagnosis.
(3) Severe TTTS is reported to occur in 5.5% to17.5% of
cases. (7)
TTTS is detected ultrasonographically as fetal growth
discordance and differences in amniotic sac size, the
so-called “poly-oli” or twin oligohydramnios polyhy-
dramnios syndrome picture. In severe TTTS, the donor
twin becomes progressively hypovolemic and develops
oliguria and oligohydramnios due to decreased renal
perfusion as well as abnormal umbilical artery Doppler
velocimetry. The oligo-/anhydramnios of the donor
twin may become so severe as to inhibit fetal movement.
As the fetus becomes more closely enwrapped in its
amnion, it appears “stuck” to the uterine sidewall or its
placenta (ie, “stuck twin” syndrome.) The recipient twin
becomes hypervolemic and hypertensive, which leads to
polyuria and polyhydramnios. The recipient is character-
istically larger, with cardiomegaly/visceromegaly (Fig.
1), and may exhibit abnormal venous Doppler study
results due to progressive ventricular hypertrophy and
worsening diastolic compliance. Both twins are affected
adversely in TTTS. Hydrops fetalis may develop in either
twin, but congestive failure is seen most commonly in the
recipient. Left untreated, severe TTTS has an 80% to
100% mortality rate, particularly if it is detected before
20 weeks of gestation. (8)(9)
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neonatology twin-to-twin transfusion syndrome
Figure 1. Briefly formalin-fixed autopsy heart-lung bloc
specimens from 1-day-old, 29-week gestational age twins
with history of TTTS. The donor twin’s (D) heart-lung bloc is
smaller and paler than the recipient’s (R). The recipient’s heart
has been opened along the right ventricular outflow tract into
the pulmonary artery, and both blocs show some sectioning of
the lungs. The marked ventriculomegaly and blunting of the
cardiac apex are apparent. Modified from Faye-Petersen, et al
(23) and used with permission.
Prior to ultrasonography, the criteria for diagnosing
TTTS were derived from neonatal experience with the
condition in which a greater than 5.0-g/dL (50.0-g/L)
difference in neonatal hemoglobin value and greater than
20% growth discordance was seen between the twins.
However, these classic discrepancies between weight and
hemoglobin values now are appreciated to occur in 25%
or fewer of cases detected by ultrasonography. (9)(10)
For example, hemoglobin discrepancy frequently is not
observed at midgestation, and severe TTTS may exist
prior to observing a 20% or greater fetal weight discor-
dance. (9) As described previously, cases of intrauterine
death of the donor twin may result in acute net blood
flow reversal, with the smaller, deceased twin suddenly
becoming plethoric and the former recipient becoming
pale and anemic. (11) The severity of TTTS has been
described via a number of systems, notably the clinical
stages proffered by Quintero and associates (12) and
later modified by Harkness and Crombleholme. (9)
Pathogenesis of TTTS
Ultrasonographic, ex vivo and in vivo placental, mathe-
matically derived vascular models and fetal and neonatal
blood sample studies have revealed TTTS to be a com-
plex and dynamic pathologic condition. In addition to
the inter-twin vascular connections, fetal biochemical,
humoral, and functional adaptations also appear to be
determinants of TTTS onset and progression. (1)(8)
(9)(10)
Placental Structure
TTTS is believed to develop because all DiMo twins
initially share the chorion, the extraembryonic mesen-
NeoReviews Vol.9 No.9 September 2008 e371
neonatology twin-to-twin transfusion syndrome

occurring at the villous capillary

level have been implicated as the
major determinants of the imbal-
anced shunting of blood occurring
in TTTS. (1)(3)(5) The reader is
referred to a collective discussion
among major investigators of
TTTS, (15) but at least 80% of
cases of TTTS have been attributed
to imbalances in the number, size,
and direction of deep A-V anasto-
moses.
Because of the putative major
role of inter-twin anastomoses,
Figure 2. Diagram of the anastomoses in a DiMo placenta. The right umbilical cord is from most investigations of TTTS have
the donor twin (II) and the left umbilical cord from the recipient (I). The chorionic plate been directed toward study of the
shows arterioarterial (A-A) and venovenous (V-V) superficial anastomoses. Normally, each DiMo placental vasculature. Stud-
arterial branch of the chorionic plate is paired with a venous vessel. However, in the
ies generally have identified a pau-
so-called “deep anastomosis,” an unpaired artery (blue for relatively low oxygenated
city of anastomoses as a prominent
blood) from one twin (II in the diagram) supplies a portion of the chorionic villous tree
that is drained by an unpaired vein from the co-twin (I in the diagram) (red to signify risk factor in the development of
better oxygenated blood.) TTTS. Paucity, especially of deep
anastomoses, leads to fewer
chances for volumetric balance in
chyme. This layer differentiates into connective tissue cross-circulation between the twins. Larger numbers of
stromal plugs that develop vascular cores through vascu- superficial chorionic anastomoses, particularly arterio-
logenesis, which successively branch, via angiogenesis, to arterial (A-A) connections, appear to confer relative pro-
form the chorionic villous tree. Thus, although each twin tection against the development, early onset, or severity
has its own umbilical cord vessels and acquires its own of TTTS. (9)(15)(16)(17)(18) However, the “protec-
connections to and exerts its own influences on the tive effect” of these A-A anastomoses remains somewhat
developing vascular territories within the placenta, DiMo controversial. Venovenous (V-V) connections comprise
twins theoretically have numerous “opportunities” for a lower percentage of anastomotic types found in DiMo
vascular connections (chorangiopagus vessels) to form gestations and have been associated with poorer perinatal
and persist as sites of “third” circulation. (1) Indeed, outcome. V-V anastomoses are seen in 20% of DiMo
several ex vivo injection studies have demonstrated such placentas, A-A in 75%, and A-V in 70% by clinical and
anastomoses, (13) and studies using erythrocytes, pan- pathologic studies, but fetoscopic studies have shown
curonium, and microbubble contrast agents as markers, that 95% of anastomoses are A-V. (15)(19) However,
as well as color Doppler studies, have provided in vivo some investigators have proposed that V-V anastomoses
evidence. (10) At least 85%, if not essentially all DiMo may provide compensatory reversal of blood flow in
twins, have sites of shared circulation. (10)(13)(14) The some situations. (15) Presumably, as the recipient’s cen-
shared villous tree has been shown to consist of direct, tral venous pressure rises with hypervolemia and ensuing
superficial anastomoses between the twins’ umbilical congestive failure, the V-V anastomoses may be “protec-
cord branch vessels on the chorionic plate surface and tive” to both twins by helping to alleviate right ventric-
“deep” sites, wherein the arterial ramifications from one ular failure in the recipient and theoretically shunting
twin’s cord pierce the chorionic plate to supply a por- blood back to the venous system of the donor. The
tion(s) of the villous tree that is drained by the venous relatively fewer numbers of V-V connections, in addition
system of its co-twin (Fig. 2). (Chorionic plate arterial to their anatomy and lower pressure differential, may be
and venous vessels are normally paired, but in a region of determinants of how effectively they contribute to bal-
shared villous tree in a DiMo placenta, the afferent artery ancing inter-twin blood flow.
from the donor is unpaired, as is the efferent vein of the Some researchers’ observations that the average num-
recipient.) The unidirectional “deep” arteriovenous bers of superficial vascular connections are not signifi-
(A-V) anastomoses within the placental cotyledons and cantly different between gestations involving severe

e372 NeoReviews Vol.9 No.9 September 2008

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TTTS and those that do not (14) and the fact that 80% to
90% of DiMo twins do not develop TTTS has led other
investigators to propose that more than numerical differ-
ences in anastomoses is involved in the pathogenesis
TTTS. Recent evidence suggests that vascular diameter
and resistance and the pattern of chorionic plate vascular
branching are important factors. Umur and associates,
(17)(20) using a complex mathematical computer
model, determined that, for a given radius, an A-A
anastomosis has lower resistance than the equally sized
afferent artery of an A-V anastomosis, which might ex-
plain the apparent protective effect of A-A anastomoses
noted in most studies of TTTS. By their calculations,
blood flow could be balanced more efficaciously through
an A-A anastomosis than through oppositely directed
A-V anastomoses, even though the pressure gradient in
the A-V anastomoses was greater.
De Paepe and colleagues (16) studied the chorionic
plate branching pattern in DiMo placentas from gesta-
tions without TTTS and those affected by severe TTTS.
They found that gestations involving severe TTTS were
more likely to exhibit chorionic magistral or a mixed
magistral and diffuse pattern than unaffected gestations
(60% versus 44%). The presence of a magistral pattern
(a chorionic vascular pattern composed of relatively
large-caliber, sparsely branching vessels that extended
from the cord insertion site to the placental periphery
without significant diminution in diameter), even when
mixed with the more favorable disperse pattern (charac-
terized by progressive and relatively uniform, dichoto-
mous, fine branching of vessels from the cord insertion
site, with the smaller and smaller subdivisions extending
to the placental periphery), also was associated with
higher incidences of other placental anatomic features
implicated in the development of TTTS, such as unequal
distribution of vascular territory and marginal or vela-
mentous cord insertions. In addition, donor twins were
more than twice as likely to have the magistral or mixed
pattern as recipients, and when one or both twins had the
magistral or mixed pattern, the average number of inter-
twin anastomoses was fewer. These investigators sug-
gested that the predominance of magistral and mixed
patterns in the donor twins’ placentas may be related to
the observations that magistral patterns in singleton pla-
centas are associated with absent end-diastolic blood
flow (AEDF) in the umbilical arteries (UAs). AEDF has
been attributed to the effects of a smaller peripheral
vascular tree that results in increased vascular resistance
to forward flow from the UAs. The low end-diastolic
flow in the donor’s UAs combined with the magistral/
mixed pattern might result in preferential routing of
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neonatology twin-to-twin transfusion syndrome
blood flow through anastomoses to the recipient twin.
Thus, evidence supplied by the various placental struc-
tural studies of TTTS indicates vascular resistance, cross-
sectional area, and other hemodynamic factors are con-
tributing elements in the development, timing of clinical
onset, and severity of TTTS. (8)
Unequal sharing of the placental disc is an additional
risk factor for the development of TTTS. (1)(18) How-
ever, when and how disk inequality develops is unclear.
The early developing chorionic villous tree may connect
preferentially to the vasculature of the umbilical cord of
one twin over that of the other. With unequal division of
the inner cell mass, one embryo may develop a larger
heart and, thereby, greater stroke volume and cardiac
output, such that its perfusion of the developing villous
tree initially is more robust. (1) However, others have
proposed that unequal sharing may reflect abnormalities
of placentation. Not all twin pairs that have TTTS exhibit
significant growth discordance, and there is evidence that
abnormalities of placentation may be relatively more
responsible for the growth discordance in TTTS than
imbalances in inter-twin transfusion. (21) Approximately
20% of cases of TTTS have concomitant evidence of
placental insufficiency that usually, but not always, affects
the donor twin. (22) The combination of placentation
anomalies, flow inequalities, and fetal response may de-
termine whether the donor’s placental territory appears
grossly pale and bulky (Fig. 3) (with edematous large villi
containing increased Hofbauer [chorionic villous macro-
phage] cells and nucleated fetal erythrocytes characteris-
tic of fetal anemia) or whether it is pale and atrophic-
appearing, with small villi. (3)(11)(23) Conversely, the
recipient’s parenchymal territory usually is deep red-
brown and firm due to villous congestion, but it also may
show microscopic villous edema if the fetus is in conges-
tive failure.
Marginal or velamentous cord insertions or single
umbilical artery are associated with increased risks of the
development and severity of TTTS. (1)(11)(16)(24) Of
note, although DiMo twins comprise 20% of twin gesta-
tions, they have significantly increased rates of cord
anomalies over diamniotic dichorionic twins, with more
than 50% of marginal cord insertions, more than 40% of
velamentous cord insertions, and nearly 50% of all single
umbilical artery cases occurring in DiMo twins. (25)
DiMo twins, therefore, are at constitutively increased
risks for the underlying morbidity and mortality associ-
ated with cord compression, cord accident with throm-
bosis, and vessel rupture. Such cord events could com-
pound any underlying risks of chorangiopagus, especially
NeoReviews Vol.9 No.9 September 2008 e373
neonatology twin-to-twin transfusion syndrome

Figure 3. A DiMo placenta from clinically diagnosed case of “stuck twin syndrome” wherein Twin 1 (single cord clamp) was clinically
designated as the donor Twin and Twin 2 (two cord clamps) as the recipient. A. The chorionic plate, with the donor twin side (D)
on right showing a thin cord and the recipient side (R) on left having a thick, edematous cord segment. Note the large vessels that
course under the transparent dividing membrane. B. The chorionic plate in 3A after the amnion and dividing membrane have been
peeled from its surface to expose the vessels. The donor, Twin 2 (D), has an unpaired arterial vessel that courses to a shared lobule
(arrow) that is drained by a vein from the recipient (R), when the vessel is traced back proximally toward the cord insertion site of
Twin 1. Further examination revealed several other deep anastomoses of smaller caliber that had the “expected” donor-to-recipient
arteriovenous (A-V) arrangement as well as some small “reversed” recipient-to-donor A-V-directed connections and some
arterioarterial (A-A) anastomoses. C. An A-A anastomosis (white arrow) between a donor artery (yellow arrow) and a recipient artery
(blue arrow). Images 3A–C underscore the importance of a thorough pathologic examination in TTTS cases because the net
imbalance of the shunts ultimately contributes to the donor-recipient relationship. D. The maternal surface of a “classic” TTTS case
shows a congested recipient (R) and pale edematous donor side (D). E. The foramalin-fixed sections of the placenta in 3D (maternal
surface on left aspect of sections) shows the difference in the donor’s pale tissue and the recipient’s congested tissue. However, the
demarcation, although fairly distinct, is not a consistently transmural division, as might be suggested from the appearance of the
maternal surface. Figures 3A-D are modified from Faye-Petersen, et al (23) and are used with permission.

e374 NeoReviews Vol.9 No.9 September 2008

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for the donor twin. Donor twins are more likely to have
velamentous cord insertion than are recipients. (26)
Fetal Adaptive/Maladaptive and Placental
Responses
The asymmetric, bidirectional inter-twin exchange of
blood and its biochemical components results in hemo-
dynamic, osmotic, and physiologic changes in the fe-
tuses. (1)(8)(9)(10) Hypovolemia and decreased renal
blood flow in the donor may cause a number of renal
structural and functional aberrations, especially in severe
TTTS, including renal tubular degeneration and cellular
apoptosis, loss of glomeruli or reduction in tubular num-
ber, and maldevelopmental progression to renal dysgen-
esis. (27)(28) Renal hypoperfusion also has been linked
to activation of the renin-angiotensin system (RAS)
(27)(29)(30) and elevated antidiuretic hormone concen-
trations (31) in the donor. Donors have hyperplasia of
juxtaglomerular apparatuses, with increased numbers of
renin-secreting cells (27) and upregulation of renin syn-
thesis, (29) which are presumed to represent adaptive
responses to restore euvolemia. However, in severe
TTTS, activation of the RAS and associated elevations in
angiotensin II (AT II) likely result in AT II-mediated
fetal vasoconstriction that further compromises renal
blood flow, leading to worsening oliguria and oligohy-
dramnios. Increased fetal adrenal production of aldoste-
rone may play a contributing role. (27)(29)(30)(31)
Bajoria and colleagues (31) recently found that donors’
plasma and amniotic fluid concentrations of vasopressin
were threefold higher than those of their co-twin recipi-
ents. (DiMo twins that did not have TTTS had higher
concentrations than the recipients in TTTS, but they
were not discrepant or as elevated as the donors in
TTTS.) Thus, good evidence suggests that the oligohy-
dramnios of the donor twin is a consequence of poor
renal perfusion due to net hypovolemia, but it is exacer-
bated by vasoconstriction, mediated by AT II/
vasopressin. Fetal vasoconstriction also may reduce pla-
cental blood flow to the villous tree, which may
contribute to growth restriction in the donor.
(27)(29)(30)
In severe cases of TTTS, hypervolemic recipients have
renomegaly and glomerulomegaly consistent with in-
creased renal blood flow, and immunohistochemical
studies have revealed they have downregulation of the
RAS, with markedly reduced numbers of renin-secreting
cells and renin synthesis. (27)(29)(30) However, they
have paradoxically high concentrations of renin and al-
dosterone, and the cardiomegaly, cardiomyopathy, hy-
pertension, and nephrosclerosis seen in recipients in
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neonatology twin-to-twin transfusion syndrome
TTTS are insufficiently explained by hypervolemia alone.
Such observations are supportive evidence for transfer of
these and possibly other vasoactive effectors from the
donor to the recipient across placental anastomoses. The
hemorrhagic necrosis and microangiopathic lesions seen
in kidneys from recipients in severe TTTS also may be
related to transanastomotic passage of hormones from
the donor. (30)(32) Low concentrations of antidiuretic
hormone in the recipient, together with elevated renin
concentrations secreted by the donor, are likely respon-
sible for worsening hypervolemia and polyuria/
polyhydramnios in recipients. Maternal sequelae of fetal
elevations in vasoactive substances have been appreciated
recently. Elevated fetal renin-AT II values have been
associated with maternal pseudoprimary hyperaldoste-
ronism, (33) and it is possible that these contribute to
changes in maternal perfusion of the placental bed.
In addition to anastomotic transfer of vasoactive me-
diators, increased cardiac synthesis and secretion of na-
triuretic peptides (NPs) have been linked to the progres-
sion of TTTS. NPs are a family of biochemical mediators
that normally regulate blood pressure and body fluid
homeostasis through their diuretic, natriuretic, and va-
sodilatory effects as well exerting antiproliferative effects
on cardiovascular/mesenchymal tissue. Exploration of
their role in the pathogenesis of adult cardiac hypertro-
phy and cardiomyopathy has led to greater appreciation
of their importance in normal embryofetal development
and their role in cardiomyopathy in the recipient twin in
TTTS. In the fetus, in contrast to the adult, both atrial
natriuretic peptide (ANP) and brain natriuretic peptide
(BNP) hormones are normally at high circulating con-
centrations and are expressed at high concentrations in
the ventricles (in the normal adult, they are in expressed
at low concentrations in cardiac atria and ventricles,
respectively.) Their release is stimulated primarily by
increased myocardial stretch and volume overload, hy-
perosmolality, and hypoxia, and vasoconstrictors, such as
AT II, vasopressin, and endothelin-1 (ET-1), have been
shown to result in their increased expression and secre-
tion. ANPs and BNPs appear to be integral to embryonic
fetal salt and water and blood pressure regulation, and
the peptide system is likely functional by midgestation.
ANP and BNP also appear to be important mediators of
cardiogenesis because of their inhibitory effects on myo-
cardial and fibroblast cell proliferation. Their effects on
fetal aldosterone concentrations are unknown, but they
suppress aldosterone synthesis in the adult. A third NP,
c-type natriuretic peptide (CNP), which is found in adult
genitourinary, pituitary, and brain tissues, is not pro-
duced in any significant quantity in the fetal or adult
NeoReviews Vol.9 No.9 September 2008 e375
neonatology twin-to-twin transfusion syndrome
heart, although it is secreted by the placenta. Placental
production of NPs (ANP, BNP, CNP) affect vasorelax-
ation in the fetoplacental vasculature and likely help
regulate blood supply to and within the fetus.
ANP and BNP both bind to natriuretic receptor
NPR-A, a guanyl cyclase-linked receptor, which leads to
generation of cytosine-GMP and the cascade that results
in their physiologic effects. (34)
Bajoria and colleagues (35)(36) demonstrated that
recipient twins in TTTS have higher concentrations of
ANP, BNP, and ET-1 than their co-twin donors or
DiMo twins without TTTS and that high concentrations
of BNP and ET-1 are particularly correlated with cardiac
dysfunction in the recipient. They suggested that these
compounds might be used as early markers of cardiac
compromise. It is plausible that the immaturity of the
fetal kidney and its inability to concentrate urine may be
exacerbated by the vasodilatory and diuretic effects of
BNP and ANP released due to hypervolemia and con-
tribute to polyuria/polyhydramnios or be compounded
by BNP stimulation due to AT II transferred from the
donor. Increased ANP concentrations in blood and am-
niotic fluid have been detected in recipients in TTTS,
greater than donor twin’s and uncomplicated DiMo twin
pair’s values. Increases in ANP also are related directly to
increases in amniotic fluid volumes, and markedly in-
creased immunostaining for ANP localizes predomi-
nantly to the heart and cytoplasm of the distal convo-
luted tubules of the kidneys of recipients when compared
with measurements for donor twins. These data are
supportive evidence that polyhydramnios in the recipient
twin occurs as a consequence of ANP-mediated increases
in fetal urine output due to ANP expression in both
cardiac and renal tissues. (37)
Cardiac hypertrophy with cardiac dilatation is seen in
recipients in TTTS and likely is due to the increased
cardiac preload and increased afterload pressures due to
hypertension. (30)(38) Of note, ventricular hypertrophy
predominates and dilatation is comparatively “mild,”
with right ventricular compromise preceding and gener-
ally exceeding that of the left ventricle. (9) Although the
right ventricle is the primary “workhorse” of the fetal
heart, and fetal myocardium can proliferate, other devel-
opmental factors likely contribute to the myocardial mu-
ral thickening detected by ultrasonography. Fetal myo-
cardium is “stiffer” than the adult heart. The fetal
myocardium has a greater percentage of noncontractile
elements (60% versus 30% in the mature heart) and
relatively delayed removal of calcium from troponin C,
and the ventricles have a shorter phase of early passive
diastolic filling and a greater reliance on atrial contrac-
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tion. Fetal lamb studies have shown that after 4 to 5 mm
Hg, further atrial preload does not result in increased
stoke volume. Thus, the fetal heart is inherently and
mechanically less efficient, is less able to increase stroke
volume, and displays impaired relaxation. (39) These
effects may represent, in part, disruption of the NP
system, which has been shown to be NP receptor-
dependent in murine models. NP receptor-deficient,
Npr1⫺/⫺ knockout mice develop hypertension, cardiac
hypertrophy, and fibrosis. The absence of the receptor
effectively inhibits vasorelaxation despite elevated con-
centrations of BNP and ANP. Moreover, cardiac hyper-
trophy can result independently of the presence of hyper-
tension because the lack of receptor does not permit
inhibition of myocardial proliferation/enlargement and
fibroplasia.
The murine studies also may help to explain why
cardiac anomalies are more common in recipient than
donor survivors. Recipient twins are at increased risk for
right ventricular outflow tract obstruction and pulmo-
nary valvar stenosis/atresia with intact ventricular sep-
tum. (9) The progressive hypertrophy, reduced systolic
function, and tricuspid valvar insufficiency lead to pro-
gressive decline in flow across the pulmonary valve. In a
case in which the infant underwent surgical repair, the
trileaflet semilunar valvar anatomy was identified as nor-
mal except for adhesions of the coapted leaflets. Thus,
the pulmonary valvar stenosis/atresia in recipient twins
seems to represent a unique form of “acquired congenital
heart disease” and not a primary malformation. (9)
ANP/BNP signaling interruption may play a significant
role in the generation of cardiac hypertrophy and dys-
function. (34) The right and left ventricular myocardium
have embryologic differences, and the number of NP
receptors in the right ventricle may be inherently lower;
once proliferation and hypertrophy ensue, the right ven-
tricle may become progressively more vulnerable to the
effects of preload, afterload, and pressors.
Although cardiac dysfunction is more common and
more dramatic in recipients, decreased cardiac perfor-
mance and injury also may occur in donor twins in TTTS.
(8)(9) Protracted increase in cardiac demands and energy
expenditure, due to continued transfusion of the co-
twin, and hypoxemia and acidemia, due to the anemia
and probable shrinking efficiency of placental function,
contribute to reduced cardiac function and growth re-
striction in the donor. (8) Umbilical arterial end-diastolic
forward blood flow diminishes to become absent
(AEDF). (8)(10)(21)(38)(40) Hydrops from high-
output cardiac failure can ensue in the donor due to loss
of oncotic pressure from chronic transfusion (8) and

hypoproteinemia due to passive hepatic congestion and
reduced hepatic synthesis that reflects reduced blood
delivery to the liver (due to splanchnic vasoconstriction
and relative preservation of blood shunting through the
ductus venosus with effective bypass of the liver) and
placental insufficiency with reduced nutritional supply.
Other Molecular Mechanisms Implicated in
TTTS
Myriad other factors have been identified as determi-
nants in normal and abnormal placental development in
singleton gestations, and it is likely that aberrations in
expression, timing of onset, and duration of expression
of these angiogenic and trophotropic factors potentially
are involved in the pathogenesis of TTTS. Several appear
to have implications for the asymmetric placental and
chorionic vascular branch pattern development, placen-
tation, and fetal growth restriction in the donor twin.
Detailed discussion of these complex factors is beyond
the scope of this review, but chorionic vascular prolifer-
ation, branching, and lengthening are affected by oxygen
tension and hormonal factors that exist in the maternal
space, (1)(5)(41)(42) relative values of promoters of
angiogenesis (ie, vascular endothelial growth factor
A and placental growth factor), (43)(44)(45) popula-
tions and distributions of receptors to these growth
factors, relative concentrations of trophoblast-produced
and milieu-associated antiangiogenic determinants,
(44)(45)(46) and effects of local mediators such as nitric
oxide. (16)(47) The roles of insulin-like growth factors
and receptors, (48)(49)(50) fetally produced hormones
such as leptin, (48)(50)(51)(52) and placental inflamma-
tory mediators such as interleukin-6, -8, and -10 (5)(49)
likely will be determined to have a role in the pathogen-
esis of abnormalities associated with the vasculature,
placentation, and growth of the placenta and fetal twin
pair.
Summary
TTTS is a complex condition that results from circula-
tory imbalances due to placental anastomoses between
DiMo twins. Its date of onset, rate of progression, and
severity are multifactorial and reflect numbers and types
of anastomoses, unequal sharing of the placenta, trans-
fusion of vasoactive mediators from the donor, abnormal
expression of hormones that affect cardiac function in the
recipient, and the effects of fetoplacental vascular resis-
tance. Many of the deleterious effects of TTTS have
implications for the necessity for and responsiveness to
medical therapies for neonates born of these complicated
gestations. The intrauterine environment of TTTS, with
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neonatology twin-to-twin transfusion syndrome
its circulating mediators and shifts in blood shunted
between the twins, ultimately can affect cardiac, renal,
and hepatic function of the twins. Greater understanding
of the pathogenesis of TTTS can help neonatologists
explain the sometime confusing findings in the donor
and recipient twins.
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 neonatology twin-to-twin transfusion syndrome

NeoReviews QUIZ
1. Chronic twin-to-twin transfusion syndrome (TTTS) is a condition characterized by a sustained imbalance of
blood volume transfused between twins, with one twin becoming a donor and the other twin becoming a
recipient of the transfusion. Of the following, the most accurate statement regarding chronic TTTS is that:
A. Arterioarterial anastomoses in the placenta are associated with poorer perinatal outcome than
arteriovenous anastomoses.
B. Chronic TTTS is almost exclusively restricted to twins with diamniotic monochorionic placentations.
C. Marginal or velamentous umbilical cord insertions or a single umbilical artery lessen the severity of
TTTS.
D. Recipient twins are more likely than donor twins to have a chorionic magistral blood vessel pattern.
E. Recipient twins are more susceptible than donor twins to fetal entrapment in the amnion (“stuck twin
syndrome”).

2. In chronic TTTS, the asymmetric inter-twin exchange of blood and its biochemical components results in
hemodynamic, osmotic, and pathophysiologic changes in the fetuses. Of the following, the hormone most
likely to be upregulated in the recipient twin in chronic TTTS is:
A. Aldosterone.
B. Angiotensin II.
C. Arginine-vasopressin.
D. Atrial natriuretic peptide.
E. Renin.

NeoReviews Vol.9 No.9 September 2008 e379

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 Twin-to-Twin Transfusion Syndrome: Part 1. Types and Pathogenesis
Ona M. Faye-Petersen and Timothy M. Crombleholme
NeoReviews 2008;9;e370-e379
DOI: 10.1542/neo.9-9-e370

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