What—and Why—the Neonatologist Should Know

About Twin-To-Twin Transfusion Syndrome

Joseph M. Bliss, MD, PhD,*† Stephen R. Carr, MD,*‡ Monique E. De Paepe, MD,*x Francois I. Luks, MD, PhD*{
*The Fetal Treatment Program of New England and the Divisions of †Neonatology, ‡Maternal-Fetal Medicine, xPediatric and Developmental Pathology,
and {Pediatric Surgery, Alpert Medical School of Brown University, Providence, RI

Education Gaps
1. Clinicians may not appreciate the unique risks and potential complications
faced by monochorionic twins due to vascular connections in their shared
placenta.
2. Clinicians need to understand contemporary fetal treatment modalities available
to disrupt the pathophysiology of twin-to-twin transfusion syndrome.

Abstract
Twin-to-twin transfusion syndrome results from unbalanced vascular
anastomoses in monochorionic twin gestations. This condition, affecting
2,500 pregnancies each year in the United States, is most commonly
identified with ultrasonography on the basis of unequal amniotic fluid
volumes in a monochorionic, diamniotic pregnancy. Hemodynamic
alterations in the syndrome lead to oligohydramnios, intrauterine growth
restriction, and frequently, anemia in the “donor” twin while the “recipient”
has polyhydramnios and polycythemia. In severe cases, both twins are at risk
AUTHOR DISCLOSURE Drs Bliss, Carr, De
of developing hydrops fetalis and death. The Quintero staging system is
Paepe, and Luks have disclosed no financial
widely used to characterize the features and severity of the disease in a given relationships relevant to this article. This
pregnancy and to guide decisions regarding therapy. The advent of commentary does not contain a discussion of
an unapproved/investigative use of a
endoscopic fetoplacental surgery, which affords the possibility of laser commercial product/device.
photocoagulation of connecting placental vessels and thereby separation of
ABBREVIATIONS
the twins’ circulation, has revolutionized the management of this condition
AA artery-to-artery
and improved outcomes. The main risk of intervention is preterm premature AV artery-to-vein
rupture of membranes and subsequent preterm delivery of the twins. The BPD bronchopulmonary dysplasia
outcomes for survivors of the syndrome are generally comparable to those of FLOC fetoscopic laser occlusion of
chorioangiopagous vessels
monochorionic, diamniotic twins in general and relate primarily to the
MDA-PSV middle cerebral artery peak
degree of prematurity. systolic velocity
MoM multiples of the median
PPROM preterm premature rupture of
membranes
Objectives After completing this article, readers should be able to: TAPS twin anemia polycythemia
sequence
1. Summarize the pathophysiology and potential fetal and neonatal TTTS twin-to-twin transfusion
complications of twin-to-twin transfusion syndrome. syndrome
VV vein-to-vein

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2. Describe the prenatal screening and staging criteria used in the diagnosis
of twin-to-twin transfusion syndrome.
3. Explain how treatment modalities for twin-to-twin transfusion syndrome
have evolved and the usefulness of fetoscopic laser therapy for the disorder.
4. Review the criteria and indications for fetoscopic laser therapy.
5. Discuss how the complications of twin-to-twin transfusion syndrome
manifest in the newborn period and the likely neonatal outcomes.

INTRODUCTION absence of a “lambda” or “delta” sign where the double-layer

inter-twin amniotic membrane inserts on the placenta)
Twin-to-twin transfusion syndrome (TTTS) is a complica-
and concomitant oligohydramnios in 1 twin (the donor)
tion of monochorionic twin gestations. Because the twins
and polyhydramnios in the co-twin (the recipient). (3) The
are monozygotic and share a single placenta, vascular
degree of oligohydramnios may vary, but if there is little to
connections are virtually always present. Most often, blood
no amniotic fluid in the donor sac, the fetus is “stuck”
flow through these placental anastomoses is bidirectional and
between its membranes and the placenta—a particularly
balanced. In 10% to 15%, however, this inter-twin exchange is
striking finding if the placenta is anterior. Similarly, poly-
unbalanced: 1 fetus becomes the net donor, while the other
hydramnios can sometimes be severe, causing significant
becomes the net recipient. If the condition is severe and goes
discomfort and even respiratory difficulty in the mother. The
unchecked, both twins are at significant risk of dying in utero
differential diagnosis of isolated oligo- and polyhydramnios
or sustaining severe cardiac, neurologic, and other compli-
is extensive, and one must distinguish between discordant
cations. (1) The syndrome, which may affect as many as 2,500
growth from placental insufficiency (leading to oligohy-
pregnancies annually in the United States, is clinically rele-
dramnios in the affected twin, but normal amniotic fluid
vant in the second trimester. If it occurs before 13 to 14 weeks
volume in the co-twin) and TTTS; however, it is not uncom-
of gestation, it is likely to be undiagnosed (but may present as
mon to have TTTS and concomitant growth restriction in
single or dual intrauterine demise). In the third trimester,
the donor twin. (4)
treatment for worsening TTTS is delivery.
It is important to note that TTTS is diagnosed based
Management of midgestation TTTS has changed dra-
solely on ultrasonographic criteria. Although the donor is
matically over the last 2 decades, in large part because of the
usually anemic and the recipient is polycythemic, this is not
emergence of endoscopic fetoplacental surgery. Fetoscopic
a universal finding. Fetal blood sampling with hemoglobin
laser occlusion of chorioangiopagous vessels (FLOC) is the
determination is never indicated for the diagnosis of TTTS,
only treatment that can effectively halt the syndrome. It is
and indirect measurements of anemia, like middle cerebral
also the most invasive, and may not be necessary in all cases
artery peak systolic velocity, are not necessary and some-
of TTTS. (2) Prematurity is common in TTTS because of the
times confusing. (5)
cumulative effects of twin pregnancy, polyhydramnios, fetal
intervention and, in some cases, rescue delivery for fetal
deterioration. Neonatal management for infants affected by PATHOPHYSIOLOGY OF TWIN-TO-TWIN TRANSFUSION
TTTS is, in many ways, similar to that of gestational age– SYNDROME
matched unaffected twins. However, certain clinical findings
and complications are specific to TTTS and its treatment. The pathogenesis of TTTS remains incompletely under-
stood. If virtually all monochorionic twin fetuses share
communicating placental vessels, why do only some develop
DIAGNOSIS OF TWIN-TO-TWIN TRANSFUSION
the syndrome? The most simplistic explanation is a final
SYNDROME
common pathway that results in unidirectional net blood
TTTS is most often suspected in the presence of amniotic flow across the anastomoses, with a small number of
fluid volume discordance in a monochorionic, diamniotic anastomoses increasing the risk of imbalance: the donor
gestation. A definitive diagnosis of TTTS requires the twin gives away more blood than it receives, leading to
determination of monochorionicity (concordant gender, hypovolemia and anemia, while the recipient develops

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 polycythemia and hypervolemia. However, this long-held perfusion pressure in the dying twin may result in a steal
notion has come under scrutiny. phenomenon from surviving to dying twin, leading to pro-
Vascular communications can be artery-to-artery (AA), found hypotension in the survivor. Death of the co-twin is
vein-to-vein (VV), or artery-to-vein (AV). AV anastomoses are common (>30%) and often follows death of the first twin
deep and represent cotyledons shared by both fetuses (ar- within hours; surviving twins with chronic TTTS have a 25%
terial supply from 1 twin and venous drainage to the other). to 30% risk of severe neurologic or cardiac anomalies. (12)
AV anastomoses can be donor-to-recipient or recipient-to- Periventricular leukomalacia is the most common brain
donor, and typically, both types coexist. TTTS develops when anomaly found in survivors of TTTS and may occur even
the net flow across these multiple AV anastomoses favors a in the absence of co-twin death. Other complications
donor-to-recipient direction. AA and VV anastomoses are include vascular thromboembolic events; limb defects
superficial and connect both umbilical cords directly with- and intestinal atresia almost always occur in the recipient,
out an intervening capillary bed. The frequency of AA and have been attributed to a combination of low flow and
anastomoses is lower in pregnancies complicated by TTTS polycythemia. (13)(14)
than in non-TTTS pregnancies (25% to 57% in TTTS vs
>85% in non-TTTS). (6) This relative paucity of AA anas-
STAGING OF TWIN-TO-TWIN TRANSFUSION
tomoses in TTTS placentas has led some to believe that they
SYNDROME
act protectively (7)—a notion supported by mathematical
computer models of TTTS. (8) However, this protective Treatment options and prognosis of TTTS depend on accu-
theory does not account for the presence of AA in a sub- rate staging of the disease. Once the diagnosis of TTTS is
stantial percentage of cases with TTTS. suspected, a detailed ultrasonographic assessment, includ-
In addition to choriovascular inter-twin anastomoses, ing Doppler studies of both twins, is made to further
peripheral cord insertion and uneven placental sharing have categorize the disease. Many detailed staging systems have
been linked to an increased risk for TTTS development been proposed, often involving complex echocardiographic
in monochorionic gestations. The reported frequency of criteria to predict the true hemodynamic impact on the
peripheral (velamentous or marginal) cord insertion of at twins. (15) Nevertheless, the staging system described by
least 1 twin is significantly higher in TTTS gestations than in Quintero et al (16) in 1999 is still the most widely used today
non-TTTS gestations (52% vs 31%). (9) In TTTS gestations (Table 1). Its advantage is its relative simplicity, which
with discordant cord insertion types, it is virtually always facilitates referrals and communication between health care
the donor twin who has the peripherally inserted cord. (6) providers.
Markedly uneven placental sharing, traditionally defined as Stage I describes the amniotic fluid volume discordance—
more than 25% inter-twin difference in distribution of a deepest vertical pocket less than 2 cm in the donor sac and
placental territory, is seen in about half of TTTS gestations greater than 8 cm (or 10 cm, after 20 weeks’ gestational age)
compared with one-quarter of non-TTTS gestations. Almost around the recipient. In stage I, donor hypovolemia is still
always, the donor twin has the smaller placental share. mild, and urine production is still adequate: the bladder fills
In the recipient twin, various mediators may be modu- and is visible on ultrasonography. Once oliguria occurs and
lated in response to increased blood volume, including atrial the bladder is no longer observed to fill, the disease is
natriuretic peptide, brain natriuretic peptide, antidiuretic classified as stage II.
hormone, endothelin-1, and others. (10) Although their In stage III, one of the following is present: absent or
exact mechanisms of action remain incompletely under- even reversed end-diastolic umbilical artery flow in the
stood, these various hormonal and related mediators may donor, indicating high systemic vascular resistance and/
play a role in what some have called an exaggerated cardio- or a failing heart. In the recipient, hypervolemia and high-
vascular response to hypervolemia. output cardiac failure may lead to progressive right ventric-
Either twin can develop hydrops fetalis: the donor be- ular dilation and varying degrees of tricuspid regurgitation,
cause of anemia and high-output heart failure and the resulting in reverse blood flow through the ductus venosus
recipient because of hypervolemia. The recipient twin can and pulsatile flow in the umbilical vein.
also exhibit hypertension, hypertrophic cardiomegaly, pul- If hydrops is present in either twin (defined as the abnor-
monic stenosis, and disseminated intravascular coagulation. mal accumulation of fluid in 2 or more compartments—
Both fetuses affected by TTTS are at risk for dying; in pericardial or pleural effusion, ascites, or skin edema), the
66% of cases, the donor twin dies first. (11) Because of disease has entered stage IV. Finally, (impending) fetal
the existing fetofetal shunts, the sudden drop in arterial demise of 1 or both twins is termed stage V.

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 Despite its numerical progression, the Quintero staging criteria. TTTS appears to be less common in monoamniotic
system does not accurately predict the natural history of the twins, because of a high prevalence of compensatory AA
disease. (17)(18)(19) Not uncommonly, up- or downstaging anastomoses and shorter intercord distance, though the
occurs at random, from week to week, and the timing of condition may be underdiagnosed in this subset of patients.
progression varies widely. Nevertheless, this and other (23)
staging systems help decide the best course of action.
As originally described, the Quintero classification deter-
TREATMENT OF TWIN-TO-TWIN TRANSFUSION
mined who benefited from invasive therapy; in a small
SYNDROME
pilot study, the outcome of expectant management was
excellent in stage I, but rapidly worsened for stage II and If the syndrome is diagnosed after the gestational age of
higher, leading to the concept, still adhered to by most, that viability, close observation is the best course of action,
fetal intervention should be offered for stages II, III, and recognizing that early delivery may be necessary if the
IV. (20)(21) condition worsens. This requires weekly ultrasonography
More recently, these perspectives have been challenged. examinations and the understanding that premature de-
Some believe that a number of stage I patients (ie, without livery may be preferable to in utero deterioration. Close
evident Doppler abnormalities) may still show preclinical collaboration between maternal-fetal medicine specialists
signs of cardiovascular strain, and should really be consid- and neonatologists is therefore paramount.
ered an advanced stage. Calculating the myocardial perfor- When TTTS starts early in the second trimester, the
mance (Tei) index may help differentiate between a benign treatment options are limited. In the past, the only viable
course and an aggressive one. (22) Most recently, the notion intervention consisted of limiting the negative effects of
that nonprogressive stage I disease affords a favorable polyhydramnios (on the mother and the pregnancy). Serial
prognosis and is best observed has been challenged as amnioreduction, sometimes requiring 1 to 2 L of amniotic
well. (1) fluid to be removed from the recipient’s sac on a weekly
TTTS in the less common monochorionic, monoamni- basis, led to better fetal and neonatal outcomes than obser-
otic twin gestation will not result in discordance in amniotic vation alone. (24) Although this approach reduces the risk of
fluid volume, because the twins share a common amniotic preterm rupture of the membranes and premature delivery
cavity, making TTTS more difficult to diagnose. Diagnosis due to polyhydramnios, normalizing recipient amniotic
relies instead on discordance in size of the urinary bladders, fluid volume fails to halt the syndrome or offer long-term
abnormal Doppler patterns, and perhaps development of protection to either twin and has its own associated risk
hydrops; this situation limits the application of the Quintero of membrane rupture and unplanned delivery. Inter-twin

TABLE 1. Ultrasonographic Staging Criteria for Twin-to-Twin Transfusion

Syndrome
Stage I Oligohydramnios (<2 cm maximal vertical pocket)/Polyhydramnios (>8 cm*) Donor bladder visible
Stage II Oligohydramnios/Polyhydramnios (as in stage I) Donor bladder not visible
Stage III Oligohydramnios/Polyhydramnios (as in stage I)
Critically abnormal Doppler findings: absent or reversed end-diastolic umbilical artery flow in donor and/or pulsatile umbilical
vein flow in recipient and/or reversed flow in the ductus venosus (recipient)
Stage IV Oligohydramnios/Polyhydramnios (as in stage I)
Hydrops in either twin (‡2 of the following: ascites, pericardial effusion, pleural effusion, scalp or subcutaneous edema)
Stage V Oligohydramnios/Polyhydramnios (as in stage I)
Single or dual fetal demise

Based on the study of Quintero et al (16).

*Some centers use >10 cm after 20 weeks’ gestational age.

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 septostomy was once considered as a treatment for TTTS Fetoscopic surgery is considered minimally invasive, but
to restore amniotic fluid dynamics without the need for is still the most aggressive intervention for TTTS. It is most
repeated amnioreduction. However, the possibility of inad- often performed under local or regional anesthesia, though
vertently creating a large septostomy resulting in an essen- some offer general anesthesia as well. (27) It involves the
tially monoamniotic sac with the attendant risk of cord insertion of a 3- to 4-mm diameter cannula into the uterus
entanglement limited its usefulness. through the maternal abdominal wall, allowing the intro-
Today, the gold-standard therapy for advanced or pro- duction of a small telescope and a 400- to 600-mm diameter
gressive TTTS is FLOC. (21)(25) This procedure uses laser laser fiber. The telescope is introduced into the recipient’s
energy to photocoagulate the placental anastomoses be- sac under ultrasonographic guidance, the placental surface
tween the twins, thereby interrupting the hemodynamic is visually explored, and the placental equator is identified.
imbalance that defines the syndrome and ‘dichorionizing’ Any vessel seen crossing the inter-twin membrane at the
an initially monochorionic placenta (Fig 1). Although the equator is evaluated, and twin-twin anastomoses (AV, AA, or
goal is to halt the syndrome and improve the hemodynamic VV) are occluded using a diode or neodymium:yttrium
function of both fetuses, it also protects 1 twin against aluminium garnet (Nd:YAG) laser (Fig 2). At the end of
vascular steal in case of co-twin death. the procedure, any significant excess amniotic fluid is
The randomized Eurofoetus Trial first demonstrated removed from the recipient’s sac. (28) Specific techniques
higher survival rates after laser therapy (76% survival of may vary from center to center, but the general principles are
at least 1 twin) than with serial amnioreduction (56% the same.
survival). (21) The Eurofoetus Trial also showed the supe- In the initial nonselective approach described by De Lia
riority of laser coagulation with respect to short-term neu- et al, (29) all vessels crossing the inter-twin membrane were
rologic outcome and gestational age at delivery. A 4-week photocoagulated. It was later recognized that this included
gestational age advantage was noted at delivery (33 vs 29 paired vessels (arterial branch and venous return to the
weeks) in the laser group, which also had a 6% incidence of same twin), which were needlessly sacrificed. Selective
periventricular leukomalacia in the survivors, compared elimination of shared cotyledons only (artery from 1 twin
with 14% in the amnioreduction group. A few centers have connecting with a vein to the co-twin) led to improved
survival. (30) Further refinements in technique included
therefore advocated for fetoscopic intervention even after
the sequential approach, whereby donor artery–to–recipient
the fetuses have reached the gestational age of viability. The
vein anastomoses are coagulated first, based on the untested
Leiden group in particular has been offering intervention
notion that this will allow back flow of blood from the
well into the third trimester, claiming better neonatal out-
recipient to the donor, thereby lessening the effect of the
comes. (26)
syndrome on both fetuses. (31)
The ultimate goal of FLOC is the obliteration of all
placental communications. Although the technique is highly
successful in halting the syndrome, it has been long rec-
ognized that some vascular anastomoses persist in up to
30% of cases. (5)(6) This incomplete coagulation does not
necessarily result in persistence of the syndrome (as the flow
imbalance may have been sufficiently dampened to allow
the twins to recover). However, the theoretical risk of
recurrence, damage to a surviving twin should the co-twin
die, or even reverse TTTS (whereby the donor becomes
recipient and vice versa) led to the development of the
Solomon technique. (32) Named after King Solomon’s
legendary ruling, it consists of physically dividing the pla-
cental equator (rather than just the individual vessels) in a
Figure 1. Schematic illustration of fetoscopic surgery for severe twin-to- scorched-earth fashion, effectively separating the 2 fetopla-
twin transfusion syndrome. Donor (left) has oligohydramnios and is cental circulations. A randomized, controlled study sug-
“stuck” behind the inter-twin membrane. Endoscopic instrument is
inserted through the recipient’s polyhydramniotic sac. Laser beam gested that the Solomon technique significantly reduced
(dotted line) aims at placental anastomoses between donor and
the incidence of twin anemia polycythemia sequence
recipient. (Courtesy of Francois I. Luks, MD [CC BY-SA 3.0 (http://
creativecommons.org/licenses/by-sa/3.0)] via Wikimedia Commons.) (TAPS) and recurrent TTTS, though it increased the

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Figure 2. Fetoscopic views in twin-to-twin transfusion syndrome. A. View of donor fetus through the inter-twin membrane. Note membrane folds
tightly draped over donor’s neck. Fingers of recipient twin visible on the other side of the membrane. B. Placental vascular anatomy. Paired arteries and
veins from 1 twin. Typically, arteries lie on top of their corresponding vein. Note deoxygenated (dark) blood in arteries and bright red, oxygenated blood
in veins. C. Twin-twin anastomoses. Note 2 unpaired vessels crossing the inter-twin membrane. Laser occlusion on the recipient’s side of the membrane.
AV¼artery-to-vein.

incidence of preterm premature rupture of membranes if left untreated. Since the first randomized trial in 2004,
(PPROM). (32) (21) numerous (mostly nonrandomized) studies have shown
survival rates ranging from 70% to 90%. A recent meta-
analysis of all available series showed an average survival for
POSTOPERATIVE RESULTS
at least 1 twin of 81% (and overall survival of 67%). (35) There
Following the 30- to 60-minute procedure, the patient are several reasons for the mixed survival results. As men-
remains in the hospital for 1 to 2 days, and will require 1 tioned, some fetuses are already too sick to be able to recover
to 2 weeks of convalescence, but bedrest is not usually after FLOC. The placental share of some donors is so small
necessary. Tocolysis varies by center and can be tailored that placental vascular resistance is exceedingly high; in
to the patient, but is often required for the first few days. In those circumstances, the AV anastomoses to the recipient,
the United States, nifedipine has mostly replaced magne- although detrimental in the long run, offer a “pop-off”
sium sulfate because it is better tolerated. release by decreasing the afterload. Following FLOC, the
Ultrasonography follow-up is recommended twice a sudden rise in placental vascular resistance can worsen the
week for the first 14 days, and can usually be decreased donor’s cardiac function, leading to hydrops. Although this
to once a week thereafter. (33) The ultimate goal of therapy is can be a temporary phenomenon, it can prove fatal if the
delivery near term and intact dual survival. The procedure donor was already critically ill.
itself is highly successful in halting or altering the course Similarly, advanced disease in the recipient may preclude
of TTTS. Signs of this hemodynamic alteration can be de- recovery after FLOC. In addition to the (right) ventricular
tected as early as 2 to 5 days postoperatively: visualization strain caused by hypervolemia, recent evidence has shown
of the donor bladder, resolution of Doppler anomalies in the that in a fraction of recipients, cardiac dysfunction can be
recipient or donor umbilical vessels, and improved cardiac exacerbated by FLOC. The etiology can be attributed to
contractility and (tricuspid) valvular function in the recipient. either underlying (and preexisting) pulmonary stenosis
However, FLOC does not directly improve the fetuses’ car- or inappropriate vasoactive stimulation (through the donor)
diovascular status, and advanced fetal stress may still result in that may have created an exaggerated cardiovascular
postoperative fetal demise. The donor has an approximately response to hypervolemia, rendering the recipient more
10% survival disadvantage relative to the recipient, but both fragile.
twins are at risk for early postoperative death. (11) Unfortu- Recurrence of TTTS after FLOC has been described in
nately, predictive models are imperfect, and there is no approximately 5% of cases. (36)(37) It may be caused by
reliable method to determine impending death of either incompletely occluded or missed anastomoses, and often
twin. (34) Of note, FLOC effectively separates the fetal requires reintervention. There is even the potential risk of
circulations, and postoperative demise of 1 twin does not new flow imbalance, whereby the donor becomes recipient
have the potentially disastrous consequence for the co-twin and vice versa. The ensuing blood volume discordance
that untreated TTTS carries. (12) (whether inversed or not) can be present without the classic
Overall results of FLOC for severe TTTS are reasonably hallmarks of TTTS (absent donor bladder, amniotic fluid
good, particularly when compared with the dismal outcome discordance, Doppler anomalies). It is then referred to as

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 TABLE 2. Antenatal Staging of TAPS (39)
Stage I MCA-PSV >1.5 MoM in donor and <1.0 MoM in recipient without signs of fetal compromise
Stage II MCA-PSV donor >1.7 MoM and MCA-PSV recipient <0.8 MoM without signs of fetal compromise
Stage III MCA-PSV donor >1.5 MoM and MCA-PSV recipient <1.0 MoM with cardiac compromise of the donor (defined as critically
abnormal flow)
Stage IV Hydrops of the donor, preceded by TAPS
Stage V Single or dual fetal demise, preceded by TAPS

MDA-PSV¼middle cerebral artery peak systolic velocity; MoM¼multiples of the median; TAPS¼twin anemia polycythemia sequence.

TAPS (Table 2). (5)(38) The incidence of iatrogenic TAPS prematurity and the underlying cardiovascular strain on
varies between reports, with an average of approximately former donor and recipient. Because of smaller placental
5% to 10%. Mild to moderate TAPS (stage I or II) is best share, chronic anemia, and increased work, the donor is
observed; advanced stages may require intervention, includ- usually small for gestational age. (4) This may further
ing repeat FLOC or early delivery, depending on the gesta- complicate the management and worsen the outcome of
tional age. (39) associated hydrops. The recipient is typically appropriate or
Prematurity is very common: risk factors include twin large for gestational age, and tends to be polycythemic.
gestation (more so in monochorionic than in dichorionic Underlying pulmonary stenosis, (42)(43) cardiomyopathy,
twins), TTTS itself, polyhydramnios, (repeated) amniore- and manifestations of high-output cardiac failure (hydrops)
ductions, and endoscopic fetal surgery. (40)(41) The risk of may have an adverse impact on the outcome. Persistent or
PPROM after FLOC (also referred to as iatrogenic, or hemodynamically significant pulmonic valve abnormalities
iPPROM) ranges from 9% to 15% within the first 14 post- may require cardiac intervention. Nevertheless, prolonged
operative days, and reaches 19% to 50% by 32 weeks of evidence of (right) cardiac strain in the recipient after FLOC
gestation. Consultation with neonatologists is therefore is not necessarily associated with poor outcome, and many
important to discuss options for postnatal interventions of these infants will show gradual improvement in cardiac
should delivery ensue. Preoperative administration of function over time. Indeed, studies at age 10 years have
maternal corticosteroids should be considered for patients demonstrated little myocardial dysfunction even in those
whose infants will receive full support in the event of who had severe dysfunction in utero. (44) Both donor and
delivery. recipient twins are at risk for hypertension related to the
cardiovascular and renal adaptations to TTTS, and there-
fore, blood pressure should be monitored closely. Elevated
NEONATAL OUTCOMES
blood pressures have been reported in 62% of survivors at 2
Delivery and cord clamping effectively halts TTTS, but years of age in both donors and recipients. (45)
the syndrome may still affect the newborn and infant twins. Other TTTS-specific morbidities of the newborn include
The most common immediate problems are related to an increased incidence of renal tubular apoptosis seen in

Figure 3. Long-term outcome of twin-to-twin

transfusion syndrome. In a case-control study,
the degree of prematurity was the only
determinant of long-term outcome after
twin-to-twin transfusion syndrome that was
treated with fetoscopic surgery. The
incidence of major sequelae decreased with
increasing gestational age (GA) at birth. No
permanent sequelae were seen in children
born after 32 weeks’ GA. Categories at top:
GA at birth. BPD¼bronchopulmonary
dysplasia. (Reprinted with permission from
Kowitt et al, 2012 [48].)

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nomena, almost always in the recipient, and believed to be
4. Chmait RH, Korst LM, Bornick PW, Allen MH, Quintero RA. Fetal
a result of sluggish blood flow and polycythemia. Although
growth after laser therapy for twin-twin transfusion syndrome. Am J
rare, these complications can be severe. Limb necrosis has Obstet Gynecol. 2008;199(1):47.e1–47.e6
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infants and children after severe TTTS, with or without fetal Geburtshilfe Neonatol. 2009;213(6):248–254

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Placental findings after laser ablation of communicating vessels in
specific complications, the overall impression is that the twin-to-twin transfusion syndrome. Pediatr Dev Pathol. 2004;7
outcome of infants who suffered TTTS in utero is mostly (2):159–165
related to the degree of prematurity. (48)(49) Thus, the 7. Hack KE, van Gemert MJ, Lopriore E, et al. Placental characteristics
incidence of mild and severe neurologic abnormalities, of monoamniotic twin pregnancies in relation to perinatal outcome.
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(50) lung disease, and complications is similar to that of
8. van den Wijngaard JP, Umur A, Ross MG, van Gemert MJ. Twin-
unaffected twins of similar gestational age at birth (Fig 3).
twin transfusion syndrome: mathematical modelling. Prenat Diagn.
(48) A meta-analysis of studies evaluating neurodevelop- 2008;28(4):280–291
mental outcome among twins treated with FLOC showed a 9. De Paepe ME, Shapiro S, Hanley LC, Chu S, Luks FI. Correlation
rate of neurologic morbidity of 6% at birth and 11% at follow- between cord insertion type and superficial choriovasculature in
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donor and recipient twins. (51) Cerebral palsy was the most
10. Bajoria R, Ward S, Chatterjee R. Brain natriuretic peptide and
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rates for monochorionic, diamniotic twins in general, (52) 11. Muratore CS, Carr SR, Lewi L, et al. Survival after laser surgery for
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chorionicity and/or prematurity rather than TTTS or its
12. O’Donoghue K, Rutherford MA, Engineer N, Wimalasundera RC,
treatment. Regardless, close neurodevelopmental follow-up
Cowan FM, Fisk NM. Transfusional fetal complications after single
is important for these patients, with implementation of intrauterine death in monochorionic multiple pregnancy are
services as appropriate to maximize positive outcomes. reduced but not prevented by vascular occlusion. BJOG. 2009;116
(6):804–812
13. Carr SR, Luks F, Tracy T, Plevyak M. Antenatal necrotic injury in
severe twin-to-twin transfusion syndrome: a case and review. Fetal
Diagn Ther. 2004;19(4):370–372
American Board of Pediatrics 14. Lopriore E, Lewi L, Oepkes D, et al. In utero acquired limb ischemia
Neonatal—Perinatal Content in monochorionic twins with and without twin-to-twin transfusion
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• Know the potential fetal complications of multiple gestation such 15. Shah AD, Border WL, Crombleholme TM, Michelfelder EC. Initial
fetal cardiovascular profile score predicts recipient twin outcome in
as cord problems, twin-twin transfusion, “stuck twin,” conjoined
twin-twin transfusion syndrome. J Am Soc Echocardiogr. 2008;21
twins, etc.
(10):1105–1108
• Know the implications and treatment options for the surviving 16. Quintero RA, Morales WJ, Allen MH, Bornick PW, Johnson PK,
fetus when its twin dies in utero. Kruger M. Staging of twin-twin transfusion syndrome. J Perinatol.
1999;19(8 Pt 1):550–555
17. O’Donoghue K, Cartwright E, Galea P, Fisk NM. Stage I twin-twin
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relation to outcome. Ultrasound Obstet Gynecol. 2007;30
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expectant management for stage I twin-twin transfusion syndrome. Ther. 2004;19(3):301–304
Am J Obstet Gynecol. 2016;215(3):346.e1–346.e7 19. Dickinson JE, Evans SF. The progression of disease stage in twin-
2. Chmait RH, Quintero RA. Operative fetoscopy in complicated twin transfusion syndrome. J Matern Fetal Neonatal Med. 2004;16
monochorionic twins: current status and future direction. Curr (2):95–101
Opin Obstet Gynecol. 2008;20(2):169–174 20. Quintero RA, Dickinson JE, Morales WJ, et al. Stage-based
3. Hecher K, Diehl W, Zikulnig L, Vetter M, Hackelöer BJ. Endoscopic treatment of twin-twin transfusion syndrome. Am J Obstet Gynecol.
laser coagulation of placental anastomoses in 200 pregnancies with 2003;188(5):1333–1340

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 21. Senat MV, Deprest J, Boulvain M, Paupe A, Winer N, Ville Y. Endoscopic 38. Lopriore E, Slaghekke F, Oepkes D, Middeldorp JM,
laser surgery versus serial amnioreduction for severe twin-to-twin Vandenbussche FP, Walther FJ. Hematological characteristics in
transfusion syndrome. N Engl J Med. 2004;351(2):136–144 neonates with twin anemia-polycythemia sequence (TAPS). Prenat
22. Rychik J, Tian Z, Bebbington M, et al. The twin-twin transfusion Diagn. 2010;30(3):251–255
syndrome: spectrum of cardiovascular abnormality and 39. Tollenaar LS, Slaghekke F, Middeldorp JM, et al. Twin anemia
development of a cardiovascular score to assess severity of disease. polycythemia sequence: current views on pathogenesis, diagnostic
Am J Obstet Gynecol. 2007;197(4):392.e1–392.e8 criteria, perinatal management, and outcome. Twin Res Hum Genet.
23. Paepe ME. Examination of the twin placenta. Semin Perinatol. 2016;19(3):222–233
2015;39(1):27–35 40. Maggio L, Carr SR, Watson-Smith D, et al. Iatrogenic preterm
24. Mari G, Roberts A, Detti L, et al. Perinatal morbidity and mortality premature rupture of membranes after fetoscopic laser ablative
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International Amnioreduction Registry. Am J Obstet Gynecol. 41. Petersen SG, Gibbons KS, Luks FI, et al. The impact of entry
2001;185(3):708–715 technique and access diameter on prelabour rupture of membranes
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26. Middeldorp JM, Lopriore E, Sueters M, et al. Twin-to-twin Vandenbussche FP, Walther FJ. Congenital heart disease in twin-to-
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27. Duron VD, Watson-Smith D, Benzuly SE, et al. Maternal and fetal 43. Moon-Grady AJ, Rand L, Gallardo S, et al. Diastolic cardiac
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BM, Luks FI. Laser ablation of placental vessels in twin-to-twin Intertwin cardiac status at 10-year follow-up after intrauterine laser
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laser ablation of placental vessels in severe previable twin-twin 45. Pruetz JD, Schrager SM, Wang TV, et al. Blood pressure evaluation
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30. Quintero RA, Morales WJ, Mendoza G, et al. Selective e1–e7
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34. Skupski DW, Luks FI, Walker M, et al. Preoperative predictors of 2009;201:291.e1–e5
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syndrome in the Netherlands. Fetal Diagn Ther. 2007;22(3):190–194 neurodevelopmental outcome of monochorionic diamniotic twin
37. Ville Y. Technical and ethical issues in fetal therapy. Semin Fetal gestations: a multicenter prospective cohort study from the first
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NeoReviews Quiz
There are two ways to access the journal CME quizzes:
1. Individual CME quizzes are available via a handy blue CME link in the Table of Contents of any issue.
2. To access all CME articles, click “Journal CME” from Gateway’s orange main menu or go directly to: http://www.
aappublications.org/content/journal-cme.

1. A woman with twin gestation is undergoing evaluation for 1 twin having oligohydramnios. NOTE: Learners can take
There is concern for twin-to-twin transfusion syndrome (TTTS). Which of the following NeoReviews quizzes and
statements regarding diagnosis of TTTS is appropriately stated? claim credit online only
A. In dichorionic twin pregnancies, there is a 30% to 50% chance of TTTS being at: http://Neoreviews.org.
diagnosed, with higher likelihood when the twins are of opposite sexes.
B. The presence of a positive “lambda” or “delta” sign is highly suspicious for TTTS. To successfully complete
C. In most TTTS cases, both twins have oligohydramnios. 2017 NeoReviews articles
D. TTTS is diagnosed based solely on ultrasonographic criteria. for AMA PRA Category 1
E. Fetal blood sampling of TTTS is required for definitive diagnosis of TTTS. CreditTM, learners must
2. A woman with monochorionic, diamniotic twin pregnancy is diagnosed with probable demonstrate a minimum
TTTS. Oligohydramnios is noted in 1 twin and polyhydramnios in the other. If TTTS is performance level of 60%
present, which of the following statements regarding this pregnancy is most likely to be or higher on this
correct? assessment, which
A. There is likely to be a balanced net blood flow across communicating placental measures achievement of
vessels. the educational purpose
B. The frequency of artery-to-artery anastomoses is typically higher in pregnancies and/or objectives of this
complicated by TTTS than in non-TTTS pregnancies. activity. If you score less
C. If artery-to-vein anastomoses are present, they are likely to be deep and represent than 60% on the
cotyledons shared by both fetuses, with both donor-to-recipient and recipient-to- assessment, you will be
donor communication coexisting, with the net flow favoring donor-to-recipient. given additional
D. There is less likelihood of peripheral cord insertion compared with non-TTTS opportunities to answer
gestations, but if it is present, will most likely be found in the recipient twin. questions until an overall
E. If there is fetal demise, it will most likely occur first in the recipient twin. 60% or greater score is
achieved.
3. A woman with twin gestation undergoes ultrasonographic evaluation. The findings are as
follows: both twins are alive with normal heart rate; there is no ascites, skin edema, or
pleural effusion in either twin; the donor twin has no end-diastolic umbilical artery flow; the This journal-based CME
donor bladder is not seen during the entire 30-minute ultrasound evaluation, and the activity is available
recipient twin appears to have moderate tricuspid regurgitation. Which of the following through Dec. 31, 2019,
stages (described by Quintero et al [16]) best characterizes TTTS in this pregnancy at this however, credit will be
moment? recorded in the year in
A. Stage I. which the learner
B. Stage II. completes the quiz.
C. Stage III.
D. Stage IV.
E. Stage V.
4. A twin pregnancy is diagnosed with TTTS. One twin has oligohydramnios and appears
growth restricted. The other twin has polyhydramnios. Treatment with fetoscopic laser
occlusion of chorioangiopagous vessels (FLOC) is being considered. Which of the following
correctly describes this procedure?
A. The procedure uses laser energy to photocoagulate the placental anastomoses
between the twins, which will interrupt the hemodynamic imbalance that char-
acterizes the syndrome.
B. An inter-twin septostomy is performed to restore amniotic fluid volume balance.
C. Serial amnioreduction is performed in the recipient’s sac, up to 2 L each week.
D. Watchful waiting is under way, with laser-guided ablation of artery-to-artery
connections only when discordance reaches more than 20%.
E. A stent is placed across the umbilical vessels to create a new vascular connection
from the recipient twin to the donor twin and thereby help to restore fluid balance.

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 5. Twins are delivered after FLOC for TTTS at 34 weeks’ gestational age. Which of the
following statements concerning neonatal outcomes in TTTS is correct?
A. Anemia is likely to be present in the recipient twin, with polycythemia in the donor.
B. The donor is usually appropriate or large for gestational age.
C. Prolonged evidence of right cardiac strain in the recipient after FLOC is always
associated with a poor outcome, with gradual worsening over time.
D. Renal tubular apoptosis is most commonly seen in recipient twins.
E. Both donor and recipient twins are at risk for hypertension and should receive close
blood pressure monitoring.

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 What−−and Why−−the Neonatologist Should Know About Twin-To-Twin
Transfusion Syndrome
Joseph M. Bliss, Stephen R. Carr, Monique E. De Paepe and Francois I. Luks
NeoReviews 2017;18;e22
DOI: 10.1542/neo.18-1-e22

Updated Information & including high resolution figures, can be found at:
Services http://neoreviews.aappublications.org/content/18/1/e22
References This article cites 52 articles, 1 of which you can access for free at:
http://neoreviews.aappublications.org/content/18/1/e22#BIBL
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 What−−and Why−−the Neonatologist Should Know About Twin-To-Twin
Transfusion Syndrome
Joseph M. Bliss, Stephen R. Carr, Monique E. De Paepe and Francois I. Luks
NeoReviews 2017;18;e22
DOI: 10.1542/neo.18-1-e22

The online version of this article, along with updated information and services, is
located on the World Wide Web at:
http://neoreviews.aappublications.org/content/18/1/e22

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