Children's Hospital Colorado

Twin-to-Twin Transfusion Syndrome (TTTS)

TTTSTwin-to-Twin Transfusion Syndrome (TTTS) is a disorder that affects identical twin pregnancies where the two fetuses share a placenta (referred to as a monochorionic twin pregnancy). In 15% of these pregnancies the twins have an unequal blood flow between them. Communicating vessels on the surface of the placenta and when untreated can cause complications including early delivery, neurologic damage, and even stillbirth. The diagnosis of TTTS is made using ultrasound. Once the diagnosis is made, a referral to a center that specializes in the treatment of this disease is essential in determining management as there are treatment options available for this disease.

For Patients

Twin-to-Twin Transfusion Syndrome (TTTS) is a condition only seen in identical twins that share a placenta. The twins’ blood vessels from their umbilical cords have connections on the placenta which can cause unequal sharing of blood and fluid volume between them. If significant enough, the diagnosis of TTTS can be made. With TTTS, one twin acts as the “donor” for the “recipient” twin. The “donor” twin has signs of low blood volume and little amniotic fluid with difficulty seeing the bladder due to lack of urine production. The “recipient” twin has signs of excessive blood volume and has high amniotic fluid levels and a large bladder.

If the unequal volumes are significant enough it can lead to severe complications for the twins.

At the Colorado Fetal Care Center (CFCC), we understand the stress and fear that can come from learning your babies have TTTS. Under the direction of Dr. Timothy Crombleholme, we are at the forefront of evaluation and treatment for this disease. Read more about the talented staff at the CFCC that will help your family through this journey.

Approximately 20 percent of all twin pregnancies are monochorionic, meaning the twins share one placenta, and in these pregnancies incidence of TTTS is around 15 percent. Most cases of TTTS are in twin pregnancies where they share a placenta but have two separate amniotic sacs (known as monochorionic-diamniotic); however, it can be diagnosed in monochorionic pregnancies where the twins share one amniotic sac also (known as monochorionic-monoamniotic).

Read Katie and Robert’s journey, and learn how the CFCC supported them when their twins Joey and Paul were diagnosed with twin-to-twin transfusion syndrome.

Cambruzzi Family

Ready to learn more?

See below available treatment options at the CFCC.

TTTS is a potentially treatable disease and the Colorado Fetal Care Center is one of the nation's best centers for treating babies with TTTS.

Twin-to-Twin Transfusion Syndrome Treatment

While the diagnosis of twin-to-twin transfusion syndrome (TTTS) in your pregnancy feels life-changing, there are treatment options available that may help your children thrive, both during pregnancy and after their births.

The Colorado Fetal Care Center is one of the nation’s top care centers for treating pregnancies complicated by TTTS. Dr. Timothy Crombleholme leads our TTTS program and has treated more than 1,000 cases of TTTS over his career.

Time is critical when it comes to treating TTTS, and the earlier this condition is caught the more easily it can be treated. Many treatment options are started within hours or days of diagnosis. There are a variety of treatment options for TTTS, including medication therapy, needle drainage of amniotic fluid, and laser treatment of the connecting blood vessels.

TREATMENT OPTION: Amnioreduction

Polyhydramnios, where one twin has an excessive amount of amniotic fluid surrounding it, is a complication of TTTS that can lead to premature delivery and further complications. With amnioreduction a small needle is introduced into the amniotic sac with the extra fluid under ultrasound guidance. Amniotic fluid is then removed until the amount of fluid is back to normal. This gives the benefit of decreasing abdominal pressure for the mom and may also slow the progression of the disease. In rare cases it can arrest the TTTS or even reverse it.

TREATMENT OPTION: Medical Treatment

In cases where the recipient baby has signs of heart dysfunction nifedipine can be used in order to stabilize the disease awaiting definitive therapy. Nifedipine is a medication used to treat high blood pressure. This medication is taken by the mother and crosses through the placenta to help the babies.


In severe cases of TTTS a laser surgery may be recommended. With this procedure a small scope with a camera is inserted into the uterus in order to see the abnormal vessel connections between the babies. A laser fiber is then inserted along-side the camera and used to stop the blood flow between the babies. This is considered definitive therapy for TTTS since it disrupts the blood vessel connections.

Ready to learn more?

Read about some of the CFCC’s successful surgeries through our patient stories.

For Healthcare Professionals

The lack of agreement on specific diagnostic criteria to define midgestation Twin-Twin Transfusion Syndrome / (TTTS) and the influence of older neonatal criteria have hampered understanding of its pathophysiology and slowed the development of more effective treatment strategies.

The donor twin is characterized by oliguria, oligohydramnios or anhydramnios, growth restriction and abnormal umbilical artery Doppler velocimetry. The recipient, on the other hand, is characterized by polyuria, polyhydraminos, abnormal venous Doppler, progressive cardiac dysfunction due to TTTS-cardiomyopathy.

Clinicians caring for women with monochorionic multiple pregnancies should have a low threshold for suspecting Twin-Twin Transfusion Syndrome (TTTS). Sonographic signs of monochorionic diamniotic twins include-a single placenta, a thin dividing membrane, a "T"-sign, and gender concordance.

Before ruling out monochorionic diamniotic twins in cases where no dividing membrane is seen and monochorionic/monoamniotic twins are suspected , a diligent search for a thin membrane tightly wrapped around one twin should be performed.

Sonographic Criteria Suggestive of a Twin-Twin Transfusion Syndrome

Although not all of the following sonographic criteria are necessary for a diagnosis of Twin-Twin Transfusion Syndrome (TTTS), the following findings are suggestive of the diagnosis:

  1. Monochorionicity

  2. Discrepancy in amniotic fluid between the amniotic sacs with polyhydramnios of one twin (largest vertical pocket greater than 8 cm) and oligohydramnios of the other (largest vertical pocket less than 2 cm)

  3. Discrepancy in size of the umbilical cords

  4. Cardiac dysfunction in the polyhydramniotic twin

  5. Abnormal umbilical artery or ductus venosus Doppler velocimetry

  6. Significant growth discordance (often > 20 percent)

Criteria for TTTS diagnosed in utero were initially derived from neonatal criteria relying on discordant weights (usually > 20 percent) and hemoglobin levels (usually difference of more than 5 g/dL) between the twins. But the literature demonstrates that hemoglobin discordance is often not present in TTTS at midgestation and advanced TTTS may be present before the threshold of 20 percent weight discordance is reached.

Mothers of monochorionic diamniotic twins should be alerted that rapid uterine growth, premature contractions and dyspnea may be symptoms of polyhydramnios. These symptoms should be immediately communicated to the physicians.

The differential diagnosis of TTTS includes uteroplacental insufficiency, growth disturbances due to abnormal cord insertions, intrauterine infection, preterm premature rupture of membranes of one twin and discordant chromosomal or structural anomalies of one twin.

Quintero et al. (1) proposed a staging system for TTTS that considers a sequence of progressive sonographic features. The individual stages are described as follows:

  • Stage I: polyhydramnios in the recipient, severe oligohydramnios in donor but urine visible within the bladder of the donor
  • Stage II: polyhydramnios in the recipient, a stuck donor, urine not visible within the donor's bladder
  • Stage III: polyhydramnios and oligohydramnios, as well as critically abnormal Dopplers (at least one of absent or reverse end diastolic flow in the umbilical artery, reverse flow in the ductus venosus or pulsatile umbilical venous flow), with or without urine visualized within the donor's bladder
  • Stage IV: presence of ascites or frank hydrops (fluid collection in two or more cavities) in either donor or recipient
  • Stage V: demise of either fetus. This staging system is descriptive but had not been validated as prognostically important

Taylor et al (2) applied the Quintero staging system to a population treated with serial amnioreduction, septostomy and selective reduction alone or in combination. Taylor et. al. found no significant influence of staging at presentation with survival in his conservatively treated group.

Survival was significantly poorer where stage increased rather than decreased. These authors concluded that the Quintero staging system should be used with caution for determining prognosis at the time of diagnosis, but may be better suited for monitoring disease progression.

A subsequent larger study from the same institution, however, showed that Quintero stage at presentation, at first treatment and at worst stage did in fact predict both perinatal and double survival but not survival of any twin (3). Duncombe et. al. also showed a correlation of Quintero stage at initial presentation and perinatal survival (4).

Modification of Quintero Staging System

The Quintero staging system provides a useful shorthand to describe the progression of TTTS along a spectrum of severity. However, it has potential limitations in its use in guiding therapy.

In patients who present at Stage I with only amniotic fluid discordance, it may be difficult to know with certainty if they actually have TTTS. Patients with Stage II are usually thought to be only in the early stages of the disease. The largest group, over 60% of patients, fall into Stage III. This stage, however, comprises a very broad spectrum of severity.

At one end are patients whose only hemodynamic derangement is abnormal Doppler velocimetry, and at the other end of the spectrum are patients in whom the recipient twin has severe twin-twin cardiomyopathy with severe biventricular dysfunction.

The latter patients may be premorbid without the development of hydrops (which would be Stage IV disease). We have used fetal echocardiographic assessment of the recipient twin to stage these patients. This is in keeping with the view that, fundamentally, TTTS is a hemodynamic derangement. Fetal echocardiograms can distinguish degrees of severity amongst Stage III TTTS.

Echocardiographic features include presence and severity of atrioventricular valvular incompetence, ventricular wall thickening and ventricular function as assessed by the Tei index (5, 6). In a recent series of 110 cases of TTTS, 61% of 70 Stage I patients were upstaged and 64% of 40 stage II patients were upstaged based on echocardiographic findings (7).

The upstaging of patients from Stage II to Stage III may influence counseling regarding treatment options. These echocardiographic features are also used to assess response to therapy.

If a patient is initially treated with amnioreduction, fetal echocardiography can be used to assess response to treatment and progression of TTTS. Progression may be used as an indication to move on to selective fetoscopic laser photocoagulation (Crombleholme unpublished observations).

These data prompted Crombleholme et al to purpose a modification of the Quintero staging system which would take into account evidence of TTTS-cardiomyopathy detected on fetal echocardiogram. In the staging system, the presence of mild, moderate or severe TTTS cardiomyopathy is determined on the basis of these parameters: 1) Myocardial hypertrophy; 2) Atrioventricular valve competence; 3) Tei myocardial performance index (see table). Using these parameters the presence of TTTS cardiomyopathy is designated as mild (IIIA), moderate (IIIB) or severe (IIIC). Using this approach 61% of Quintero stage I and 64% of Quintero stage II are upstaged which may explain fetal losses among these "early stage" cases of TTTS.

TTTS is a complication, of monochorionic multiple gestations, mediated through vascular communications, having differential effects on the co-twins; one twin is hyperdynamic whereas the other is hypodynamic.

The etiology of TTTS is unknown, but vascular connections on the placenta between the twins are necessary for it to occur. The majority of monochorionic twins gestations have vascular anastomoses between the co-twins, although only a percentage, ranging from 4 to 17 percent, develop TTTS. Communications between the recipient and donor twin may be artery to artery (AA), vein to vein (VV) or, most commonly,artery to vein (AV) within a placental cotyledon. Depending on the number and type of anastomoses present, the exchange of blood may be balanced or unbalanced.

Shifts in blood flow between the twins may be either acute, as in the case of co-twin demise, or chronic. A true transfusion from one twin to another is unusual in mid-gestation TTTS. Percutaneous umbilical blood sampling performed on twins with TTTS have shown identical hemoglobin values in both fetuses (8). This suggests that at midgestation, at least the pathophysiology is not a true transfusion phenomenon, but more likely the differential effects of vasoactive mediators produced by the placenta.

AV anastomoses consist of a single unpaired artery carrying blood from one twin to a placental cotyledon and a single unpaired vein transporting blood from that cotyledon to the other twin. Most likely, AV anastomoses are primarily responsible for exchange of blood serum and vasoactive mediators from the recipient to donor twin and vice versa (9).

Bidirectional AA anastomoses, on the other hand, are thought to be protective and, if present in sufficient numbers, able to compensate for the AV mediated intertwin transfusion;VV anastomoses may also be protective although shunt less blood due to a lower pressure differential.

Recent evidence, in fact, suggests that ultrasound detection of an AA anastomosis confers a survival advantage in  TTTS independent of Quintero stage (3). The patients in the study of Tan et al. were treated with various methods including: Serial amnioreduction, Septostomy, Bipolar cord occlusion and laser ablation. Multiple logistic regression failed to show that first-line treatment modality predicted survival after correction for stage.

For stages I, II and III, detection of an AA anastomosis predicted better perinatal (100% versus 63%, 100% versus 59%, 83% versus 44%, presence of AA anastomosis versus absence of AA anastomosis, respectively) and double survival rates (100% versus 52%, 100% versus 46%, 78% versus 26%). These authors suggested the use of a modified Quintero staging system incorporating the presence or absence of an AA anastomosis.

There is mounting evidence, however, that the pathophysiology of TTTS is more complex than mere volume shifts between co-twins. For example, changes in the renin-angiotensin system compound the renal changes initiated by hemodynamic changes in the donor and recipient (6).

Angiotensin II helps to compensate in the setting of volume depletion. In the presence of TTTS, however, the intrarenal vasoconstriction mediated by angiotensin II following upregulation of renin synthesis and release may exacerbate oligohydramnios. Donor fetuses, after demise, have increased renin synthesis and renal tubular dysgenesis (10). While recipient fetuses demonstrate down regulation of renin expression, glomerular and arterial lesions in the kidneys are suggestive of hypertension-induced microangiopathy.

These findings suggest that hypertensive changes in the recipient twin may be due to vascular shunting of renin from the donor (10). It is not clear whether alterations in the renin-angiotensin system are primary or secondary effects of TTTS.

Consistent with the hypothesis, hypertensive mediators play an important role in TTTS, is the finding of Bajoria et al. Elevated levels of endothelin-1, a potent vasoconstrictor, in the serum of recipient twins are 2. 5-fold higher than in donor twin (11). Moreover, plasma endothelin-1 levels are significantly higher in the recipient twins with hydrops than in those with mild or no hydrops (11).

Endothelin-1 may also be important for the regulation of amniotic fluid volume, both by itself, and in the pathway leading to higher human brain natriuretic peptide (hBNP) levels in amniotic fluid (12).

Both endothelin-1 and hBNP amniotic fluid levels correlate with amniotic fluid index in TTTS. Recipient twin amniotic fluid levels of endothelin-1 and hBNP are the highest, followed by amniotic fluid levels from non-TTTS monochorionic twins, then by amniotic fluid levels from donor twins (12).

We believe that high levels of vasoactive mediators are preferentially shunted to the recipient twin resulting in hypertension and hypertensive cardiomyopathy.

Interruption of vascular communications by selective fetoscopic laser photocoagulation may eliminate the hypertensive stress in the recipient twin by preventing vasoactive mediators from (crossing to the recipient). We have demonstrated that donor twins have evidence on fetal echocardiograms of hypertension. Recipient twins develop AV valve incompetence and estimates of RV pressure can be made from these regurgitant jets. It is common to see RV pressures > 50 mmHg and even > 100 mmHg in fetuses with TTTS cardiomyopathy.

Consistent with this vasoactive mediator hypothesis, we have seen the development of hypertension and hypertensive cardiomyopathy in some donor twins following successful fetoscopic laser photocoagulation. Presumably the vasoactive mediators are shunted in reverse toward the donor twin in these cases.

In twins with TTTS treated by selective laser photocoagulation, we have echocardiographically observed postoperative resolution of these hypertensive changes in the recipient over weeks to months.

Echocardiographic changes associated with TTTS cardiovascular compromise occurs in most recipient twins and is a major cause of death for these fetuses (6).

In addition, cardiovascular disease in the recipient twin is a significant contributor to morbidity and mortality in the donor co-twin. Echocardiographic examination of the twins is thus an essential component of the initial work-up of TTTS as well as follow-up evaluation for progression of the disease. In addition, study of short-term and long-term cardiovascular effects of various therapeutic interventions is critical.

Recipient twins can develop a progressive cardiomyopathy. Although both ventricular dilation and myocardial hypertrophy may occur, the latter predominates and typically only mild evidence of dilatation is seen (6, 13).

Usually the right ventricle (RV) is compromised first and to a more significant degree than the left ventricle (LV) (13). In one study of 28 women with TTTS who received echocardiographic evaluation prior to any intervention, right ventricular and/or left ventricular hypertrophy was detected in 58 percent of recipient twins, and biventricular hypertrophy was observed in 33 percent of recipient twins (6).

Biventricular diastolic dysfunction was present in two thirds of recipient twins whereas right ventricular systolic dysfunction was present in 35 percent (6). Atrioventricular valve disease is also common with moderate insufficiency reported in 71 percent of recipient twins with structurally normal hearts (14).

Moderate to severe tricuspid and mitral valve regurgitation is more common in Quintero stage III and IV patients (6). Peak velocity of tricuspid and mitral regurgitant jets suggests the presence of ventricular hypertension in echocardiographic data from 39 recipient twins (14).

Estimates of RV systolic pressure based on tricuspid regurgitant jet velocity are commonly elevated to 60 to 80 mm Hg, and pressures in excess of 100 mm Hg can be seen in severe cases.

Finally, cases of acquired pulmonary atresia/stenosis with intact ventricular septum have been described in the recipient twin (6, 15). In our own series, we have seen 53 such cases with varying degrees of functional pulmonary stenosis or pulmonary atresia among 610 cases of TTTS with an incidence of 87%. Worsening RV hypertrophy, reduced RV systolic function and severe tricuspid regurgitation result in progressively diminished flow across the pulmonic valve, resulting in stenosis or atresia. In patients undergoing postnatal cardiac surgery, a structurally normal pulmonary valve is usually found with adhesed valve leaflets. These observations are not consistent with primary structural heart disease but rather acquired valvular atresia/stenosis related to TTTS, a unique form of "acquired congenital heart disease".

Cardiovascular changes in the donor twin are usually less dramatic. Myocardial changes are rare, and ventricular function and atrioventricular valve competence are usually preserved (12). In several series of patients, absent or reversed end diastolic flow was noted prior to treatment in 12 to 39 percent of donor twins (16, 17, 18, 19). The abnormalities in umbilical artery velocimetry are reversible; among survivors after laser therapy, 27-30 percent showed reappearance of end diastolic flow within 24 hours post-operatively (17, 18). Abnormal umbilical artery Dopplers are more common in the donor twin than in the recipient twin.

There is a paucity of information concerning the long-term cardiovascular implications of TTTS. In addition, data on the effect of various treatment modalities for TTTS on cardiovascular compromise and progression is lacking. If treatment, whether amnioreduction or laser photocoagulation therapy, is successful there should be an arrest in the progression of TTTS cardiomyopathy and even reversal of existent disease.

Progression of the cardiac findings suggests treatment failure either due to lack of response to amnioreduction or to a missed vascular connection with fetoscopic laser treatment. Specifically, progressive changes noted after amnioreduction include worsening hypertrophy of the right, left or interventricular septum (6, 20, 21).

Finally, discordance of pulse wave velocity in brachial arteries of survivors of TTTS is altered by laser treatment becoming more similar to dichorionic controls. The same alterations in vascular programming are not seen with survivors treated by non-laser methods (23). Increased pulse wave velocity reflects increased vascular stiffness. This study suggests that in utero vascular remodeling may be altered by definitive laser therapy.

Cardiovascular compromise occurs in most recipient twins, is a major cause of death for these fetuses, and contributes to morbidity and mortality in the donor co-twin. As early as 1992, specific recipient echocardiographic abnormalities were reported. These abnormalities are tricuspid regurgitation, ventricular hypertrophy, increased cardiothoracic ratio, and pulmonary stenosis. An echocardiographic examination of the twins is thus an essential component of the initial workup of TTTS. Then, during the antenatal and postnatal periods, follow-up evaluation for progression of the disease is also necessary. The recipient twin manifests a cardiomyopathy that is progressive in nature. At first, right ventricular dilatation and hypertrophy can be identified to a greater degree than ventricular dilatation and hypertrophy in the left ventricle. However, as the process progresses, right and left ventricular hypertrophy become more pronounced. This hypertrophy is associated with atrioventricular valve regurgitation involving first tricuspid regurgitation and then mitral valve regurgitation. Estimates of right ventricular pressures based on flow velocity of tricuspid regurgitation jet suggest that recipient cardiomyopathy is a hypertensive cardiomyopathy. Right ventricular pressures in excess of 70 mm Hg are common. The cause of this hypertensive cardiomyopathy is postulated to be due to vasoactive substances from the placenta or donor twin. The recipient twin experiences an increase in blood volume, vasoconstriction, and ventricular hypertrophy, possibly mediated by angiotensin II and endothelin-1.

The most common recipient cardiovascular abnormalities in TTTS are unilateral or bilateral ventricular hypertrophy (ranges 18%-49%), increased cardiothoracic ratio as high as 47%, ventricular dilation (ranges 17%-31%), tricuspid regurgitation (ranges 35%-52%), and mitral regurgitation (ranges 13%-15%). These abnormalities are more common with advanced stages of disease. Finally, several cases of acquired pulmonary atresia/stenosis with intact ventricular septum have been described in the recipient twin.

The reported prevalence of pulmonary stenosis in TTTS is fourfold greater than in non-TTTS. 66 The proposed pathophysiology is that worsening right ventricular hypertrophy, reduced right ventricular systolic function, and severe tricuspid regurgitation result in progressively diminished flow across the pulmonic valve, resulting in stenosis or atresia and, with increase severity, resulting in right ventricular outflow tract obstruction. The incidence of right ventricular outflow tract obstruction in TTTS is as high as 9.6%. These observations are not consistent with primary structural heart disease but rather acquired valvular atresia/stenosis related to TTTS, a unique form of "acquired congenital" heart disease. As for congenital heart diseases, there is a 15- to 23-fold higher risk of congenital heart disease with TTTS over that of singletons, and a 2.78 times more frequent occurrence of congenital heart disease in the setting of TTTS as compared to monochorionic twins without TTTS. The most common structural heart defects in TTTS twins are ventricular septal defects and atrial septal defects.

The development of TTTS in monochorionic, diamniotic gestations has significant morbidity and mortality (24,25). Currently, most centers describe severity using only the Quintero staging system. However, although recent reports have suggested that worsening Quintero stage is associated with poorer outcomes following SFLP(26), the relationship between Quintero stage and outcome remains controversial(15,16). The proposed Quintero staging assesses the severity of TTTS, focuses on changes predominantly seen in the donor twin (DT). Findings describing RT cardiomyopathy—although well described (8-12)—are not incorporated into Quintero staging, and thus, not incorporated into the formal assessment of disease severity. The more advanced findings of elevated central venous pressure found in higher Quintero stages—specifically, absence or reversal of venous flow during atrial contraction in the ductus venosus or pulsatility in the umbilical vein—has been associated with poorer RT outcome (25), suggesting a link between cardiovascular compromise and RT outcome. It was the goal of the study by Shah et al to examine the relationship between a more comprehensive assessment of fetal cardiovascular well-being, the cardiovascular profile score (CVPS), and RT outcomes.

The study, in a relatively large cohort, establishes the association between recipient twin cardiovascular status and postnatal survival. Although a relatively nonspecific predictor of recipient twin outcome, the CVPS nonetheless serves as a tool characterize degree of cardiovascular derangement. As such, use of the CVPS demonstrated that any cardiac findings, e.g., atrioventricular valve regurgitation, cardiomegaly, or ventricular systolic dysfunction are associated with poorer RT outcome. Moreover, as cardiac abnormalities "accumulate," outcomes are even worse. In the study’s series, many of the cardiac findings resulting in deductions in CVPS were not venous Doppler changes, and thereby would not be incorporated into assessment of disease severity if applying the widely utilized Quintero staging, nor would they be assessed by standard obstetric ultrasonography. Importantly, the data also demonstrated that Quintero staging did not predict RT outcome in the study population.

A comprehensive fetal cardiac assessment by echocardiography may therefore be an important component of clinical evaluation in pregnancies complicated by TTTS. For example, inclusion of cardiac findings, such as those incorporated into the CVPS, may result in a clinically useful modification of Quintero staging that could improve patient risk stratification. Such modifications have been proposed by Crombleholme, et al. (27) and Rychik et al, and would result in "upstaging" of Quintero Stage I and II when RT cardiac findings are present.

Crombleholme et al's NIH sponsored TTTS study's most important finding was that recipient twin's TTTS cardiomyopathy was the most important predictor of recipient survival.

In summary, the study establishes an association between cardiovascular abnormalities and outcome in recipient twins affected by TTTS. The findings suggest that echocardiography may have an important role in the evaluation of twin pregnancies affected by TTTS, particularly in the assessment of recipient twin cardiomyopathy (Shah et al., 2008).

A study conducted by Habli et al. (2011) describes the prevalence, severity, incidence and rate of progression of recipient twin cardiomyopathy in Stages I and II TTTS. The findings of the report suggest that early-stage TTTS may be complicated by recipient cardiomyopathy in up to 65% of cases at the-time of presentation. Among those patients who were managed expectantly or with a trial of amnioreduction, 54% progressed within a mean duration of observation of 1.4 ± 1.5 weeks. The chance of progression during expectant management or a trial of a single amnioreduction in these patients increased significantly as the degree of recipient cardiomyopathy worsened. Similarly, the rate of progression during either expectant management or trial of amnioreduction significantly correlated with the severity of recipient cardiomyopathy at initial presentation. Early-stage TTTS may be better managed by an initial period of expectant management or a trial of amnioreduction rather than proceeding directly to SFLP, as long as there is no significant recipient-twin cardiomyopathy. In this series, overall fetal survival was significantly better in the cohort (n = 80) managed initially by observation or by a trial of amnioreduction (88.0%) as compared to those managed by primary SFLP (76.7%; P = 0.02).

Recipient cardiomyopathy in TTTS is an adaptive fetal response to the hemodynamic, hormonal and biochemical stressors associated with TTTS. Several reports have shown that recipient cardiomyopathy is more common in more advanced stages of TTTS. Recently, however, Michelfelder et al.9 showed, in a cross-sectional study of cardiac evaluation of 28 consecutive early-stage TTTS patients, significant cardiac changes in recipient twins ranging between 7 and 64%. Moreover, Van Mieghem et al.18 also found, in an observational study of early-stage TTTS (Stages I and II) that 70% had echocardiographic evidence of cardiac dysfunction as well as elevated brain type natriuretic peptides, biomarkers of myocardial strain. The findings in Habli's the study are consistent with these reports - i.e. that recipient cardiomyopathy is common even in early stage TTTS, and the results suggest that even early stage TTTS cases in fact constitute a heterogeneous population with a broad range of severity of recipient cardiomyopathy, which may have a direct bearing on the natural history and response to treatment. Such findings could explain the variable natural history of early-stage TTTS cases.

In an attempt to describe the natural history of early-stage TTTS, O'Donoghue et al., in a retrospective analysis of 46 cases of Stage I TTTS, reported that 70% either regressed or remained stable. These patients tended to present at a later gestational age than did the 30% who progressed to a higher stage, within a 2-week period of observation. Dickinson and Evans similarly found that 38% of Stage I and Stage II cases regress or remain stable. Consistent with these reports, our team has found that 46% of early-stage TTTS remain stable or regress during expectant management or a trial of amnioreduction.

The importance of fetal echocardiography in the assessment of the severity of TTTS has been questioned by some groups. However, our findings in Habli's study suggest that fetal echocardiographic assessment of TTTS cardiomyopathy can be helpful in predicting not only the cases of TTTS that will progress during expectant management or a trial of amnioreduction but also how fast it will progress.

These findings suggest that fetal echocardiography in conjunction with ultrasound findings, as used in the Cincinnati staging system derived by Crombleholme, can be used to guide management options, assess response to treatment and help in better understanding the pathophysiology of TTTS. However, larger prospective studies will be needed to confirm these findings and to assess specific fetal echocardiographic features of progression with observation alone, progression despite amnioreduction and as an indication to proceed directly to fetoscopic laser treatment even in early-stage (Quintero Stage I) TTTS.

Despite the novelty of these results, they must be interpreted with caution owing to inherent limitations in the nature of the studies. A major strength of our study is that it constitutes the largest cohort of early-stage (Stages I and II) TTTS reported to date, with all patients being evaluated at the same center and managed consistently by the same team following the same management protocol. Inherent limitations include its retrospective nature, the diversity in treatment selection by patients and lack of long-term outcomes. Addressing these limitations will be the focus of future investigations.

The incidence of recipient cardiomyopathy in early TTTS (Quintero Stages I and II) is as high as 65%. Up to 46% of early-stage TTTS cases will remain stable or improve during expectant management or a trial of amnioreduction, with significantly better fetal survival as compared with those treated with primary SFLP. Conversely, 54% progressed within a mean duration of 1.4 ± 1.5 weeks based on ultrasound and fetal echocardiographic parameters. These findings provide proof of concept for the utility of fetal echocardiography in guiding the management of early-stage TTTS.

Numerous treatments for twin to twin transfusion syndrome (TTTS) have been proposed including selective reduction, cord coagulation, sectio parva, placental blood letting, maternal digitalis therapy, maternal indocin therapy, serial amnioreduction, microseptostomy of the intertwin membrane, and nonselective or selective fetoscopic laser photocoagulation.

For decades in the United States, serial amnioreduction has been the most widely accepted therapy for TTTS, but in recent years selective fetoscopic laser photocoagulation has become more accepted and in some centers is the only treatments offered.


Amnioreduction was first employed for maternal comfort and as a means to control polyhydramnios in the hope of prolonging the pregnancy until the risks of extreme prematurity were lessened.

In addition, amnioreduction improves uteroplacental blood flow, likely by reduction of pressure from the amniotic fluid.

In uncontrolled series, amnioreduction improves survival compared to the natural history of untreated Twin-Twin Transfusion Syndrome / TTTS. Moise, in a review of 26 reports dating from the 1930's of 252 fetuses, found an overall survival of 49 percent (24).

The survival in more recent series, with more consistently aggressive serial amnioreduction to reduce amniotic fluid volume to normal, have ranged widely from as low as 37 percent to as high as 83 percent (25, 26, 27, 28, 29, 30). However, these retrospective series are comprised of small numbers of patients from a range of gestational ages, as well as from a spectrum of severity of TTTS. Severity of TTTS and gestational age at diagnosis may have a profound impact on the observed mortality with any treatment strategy. Generally, the earlier in gestation TTTS presents, the worse the prognosis.

Mari et al. found that patients presenting with advanced TTTS prior to 22 weeks' gestation and absent end diastolic flow in the recipient umbilical artery had a survival of both twins with aggressive amnioreduction of only 13 percent and, with absent end diastolic flow in the donor umbilical artery, survival was 33 percent (16).


The paradoxical resolution of oligohydramnios after only a single amnioreduction was first suggested by Saade et. al. to be due to inadvertent puncture of the intertwin membrane (31).

Intertwin septostomy was specifically proposed as a treatment for TTTS to restore amniotic fluid dynamics without the need for repeated amnioreduction. One objection to this approach is the possibility it would result in a large septostomy, creating an essentially monoamniotic sac with the attendant risk of cord entanglement. In a small multicenter series of 12 patients, Saade et al. , reported an 81 percent survival with microseptostomy (32). However, not only was this series small and uncontrolled, there was no report of neurologic or cardiac morbidity. In a direct comparison, albeit a small retrospective single institution series, of serial amnioreduction versus microseptostomy, Johnson et al. observed no survival advantage with either therapy (33). This was confirmed by Saade et al. who reported the results of a multicenter prospective randomized clinical trial comparing amnioreduction to septostomy. The survival in each arm of the study was 65 percent (34) consistent with the notion that the effect of amnioreduction may be inadvertent septostomy. These studies, however, cannot prove this theory. Ultrasound guided needle technique of creating an intertwin septostomy has been abandoned, however, because of the risk of creating a monoamniotic sac and resultant cord entanglement and risk of dual fetal demise.

Fetoscopic Laser Photocoagulation

The first treatment for TTTS that attempted to treat the anatomic basis for the syndrome was reported by DeLia et al. (35, 36) who described fetoscopic laser photocoagulation of vessels crossing the intertwin membrane.

At least in theory, this treatment option should be superior since it not only arrests shunting of blood from the donor to recipient, but also halts transfer of potential vasoactive mediators. In his first small series, DeLia reported a survival of 53 percent in 26 patients (36). While survival was not significantly better than previous reports with serial amnioreduction, the "neurologic outcome" in 96 percent of survivors was "normal" as assessed by head ultrasounds. Other groups from Europe have reported similar survival with non-selective laser photocoagulation. Ville et al, reported 53 percent survival with a fetoscopic laser technique which was better than the survival observed with historical controls at the same center with serial amnioreduction (37 percent) (37). They also observed a lower incidence of abnormalities dictated by neonatal head ultrasound compared to historical controls.

The non-selective fetoscopic laser technique photocoagulates all vessels crossing the intertwin membrane. This approach may be problematic, as the intertwin membrane often bears no relationship to the vascular equator of the placenta.

This non-selective laser photocoagulation of all vessels crossing the intertwin membrane may sacrifice vessels not responsible for the TTTS, resulting in a higher death rate of the donor twin from acute placental insufficiency (38). More recently, a selective approach to fetoscopic laser photocoagulation in TTTS has been described by Quintero et al. (38).

Unlike the non-selective coagulation technique initially described by DeLia, the selective technique does not photocoagulate every vessel crossing the intertwin membrane. Only direct, arterial-arterial and veno-venous connections are photocoagulated along with any unpaired artery going to a cotyledon with the corresponding vein (and vice versa) going to the opposite umbilical cord.

Vessels on the chorionic plate can be differentiated endoscopically because arteries usually cross over veins and are darker in color due to lower oxygen saturation.

In a non-randomized comparison of patients treated by serial amnioreduction at one center and selective laser photocoagulation at another, the overall survival was not statistically significantly different (61 percent for laser vs 51 percent for serial amnioreduction) (39). However, the survival of at least one twin with laser photocoagulation was 79 percent, while survival of at least one twin with serial amnioreduction was only 60 percent (P<0. 05) (39).

The Eurofoetus trial conducted by Senat et al. (40) was the first prospective randomized trial that compares the efficacy and safety of treatment of TTTS with laser therapy versus serial amnioreduction.

Women presenting between 15 and 26 weeks gestation with polyhydramnios in the recipient twin and oligohydramnios in the donor twin were allowed to participate.

Fifty-two percent of patients were stage I or II, 47 percent were stage III and 1 percent were stage IV. Enrollment was halted after a planned interim analysis revealed a significantly higher likelihood of survival of at least one twin to 28 days of age (76 percent versus 56 percent, P = 0. 009) and to six months of age (76 percent versus 51 percent, P = 0. 002) in the laser group compared to the amnioreduction group.

More infants were alive without neurologic abnormalities detected on neuroimaging studies in the laser group as well (52 percent versus 31 percent, P = 0. 003).

The overall survival in the laser arm was 57 percent. This is consistent with previous reports of non-selective fetoscopic laser (53 percent) (36, 37). This is significantly lower, however, than the survival reported with selective fetoscopic laser (64 to 68 percent) (41, 42). Of particular concern is the poor survival which was observed in the amnioreduction arm.

The overall survival was only 39 percent, which is significantly lower than previously reported (60 to 65 percent) (16, 34). Antenatal, peripartum and neonatal care was provided by the referring hospital and lack of standardization may explain some of these differences (43).

The decreased survival in the amnioreduction group may reflect the higher pregnancy termination rate in the amnioreduction group (16 percent versus 0 percent in the laser group). The terminations were requested after the diagnosis of severe fetal complications It would be instructive to know whether these women were offered cord coagulation as a means of rescuing one baby (43).

Reliable assessment of neurologic outcome is critical when assessing efficacy of treatment for TTTS. While there was a lower rate of abnormality on neurologic imaging in the laser group (7 percent versus 17 percent), there was no long-term neurodevelopmental assessment.

Close Proximity Cotyledons

While it makes sense to use a less invasive approach to treatment if the options give similar results, it would be prudent to move promptly to laser therapy if in rigorous studies can prove laser has better short term and long term outcomes in the setting of advanced disease.

One potential limitation to the success of laser treatment is the presence of deep vascular AV anastomoses that cannot be identified endoscopically. In one study, vascular casts of 8 of 15 placentae (53 percent) demonstrated potentially significant atypical AV anastomoses such that two apparently normal cotyledons were actually communicating below the chorionic surface (9). A second type of atypical AV anastomoses was noted in 11 of the 15 placentae (73 percent) in which shared cotyledons arise within larger apparently normal cotyledons.

We are now able to identify these shared cotyledons at the time of the fetoscopic laser procedure. Paired vessels supplying cotyledons within one fetoscopic visual field should be treated as "close proximity cotyledons". When left intact, TTTS presents, and when subsequently treated, TTTS resolves. In cases in which there is very unequal placental sharing, the twin with the smaller placental share can be allowed to keep the cotyledon and the vessels to the other twin are taken.

Adjunctive Medical Treatment of TTTS

Crombleholme et al. (2010) conducted a study to evaluate the effect of maternal nifedipine on fetal survival when started 24-48 hours before selective fetoscopic laser photocoagulation (SFLP). The results of the study are the first to demonstrate that the outcome of SFLP treatment of TTTS can be influenced by an adjunctive medical therapy with the administration of maternal nifedipine. The mechanism by which the patients benefit is unclear, but the beneficial effect of nifedipine treatment appears to be specific to recipient twins, because no significant effect is observed on donor-twin survival. The specific beneficial effect of nifedipine on recipient survival that was observed in this case control study is all the more remarkable when one considers that cases of significantly more advanced-stage TTTS were included in the nifedipine-treated group (61.0% for patients with stage IIIC and IV compared with 29.6% for control subjects; P < .001). The reason for this is that there were fewer late stage (IIIC and IV) control cases available for gestational age and stage matching. We elected to use earlier-stage case controls (ie, stage IV nifedipine-treated patients matched with a control subject of the same gestational age but at an earlier stage, for example, stage IIIA or III), which by intent biased the study against the nifedipine-treatment group. Because of this matching, the overall comparison between the nifedipine cases and control subjects across stages is balanced in terms of gestational age distribution but unfavorable to the cases in terms of TTTS stage distribution. On the contrary, comparisons in each stage are not balanced in gestational age distribution and nifedipine effect may be confounded. This may account, in part, for the lack of survival advantage that was observed in patients with stages IIIC and IV. It is also possible that the severity of the TTTS cardiomyopathy in stages IIIC and IV are too advanced to respond to the brief 24-48 hours of preoperative treatment with nifedipine to affect acute fetal survival.

There is a benefit to overall fetal survival; 83% of nifedipine-treated fetuses survived compared with 75% of the control fetuses. This benefit to overall fetal survival appears to be due to improved recipient survival in mild-to-moderate TTTS cardiomyopathy in stages IIIA (100% vs 81%) and IIIB (93% vs 71%). There is also a benefit to acute survival of recipients with nifedipine treatment (92%), compared with control subjects (83%), with little change in survival to birth, which suggests that the beneficial effect is a result of better perioperative survival with nifedipine treatment. The results of this pilot study provide proof of the concept that adjunctive medical therapy, as with nifedipine, may improve survival in cases of TTTS that are undergoing SFLP.

The comparison of pre- and postoperative fetal echocardiograms, however, could not demonstrate a significant improvement in Tei myocardial performance indices for either the LVs or RVs with nifedipine treatment. This is not surprising for several reasons. First, our group has already shown that SFLP, by itself, improves fetal echocardiographic parameters and that an additional benefit of nifedipine would likely be small and require large numbers of subjects to demonstrate a benefit. Second, patients were treated for a brief period preoperatively and reassessed only 3-5 days after SFLP, which may be insufficient time to show differences in cardiac recovery between nifedipine-treated and control fetuses. Third, only acute survivors are assessed by postoperative fetal echocardiograms; sicker patients who died after SFLP fall out of this analysis. Because we demonstrated an acute survival advantage for nifedipine-treated cases, it is possible that the perioperative deaths in the control group eliminated patients that would have had worse after SFLP echocardiographic findings. Last, improvements in the Tei myocardial performance indices are small, and there is a significant variability both within and between patients, which could require large numbers of patients to demonstrate an improvement, if present, because of variability in the data. The mechanism by which nifedipine confers this survival benefit is uncertain but may make recipient twins with TTTS cardiomyopathy better able to tolerate the hemodynamic stress, altered placental resistance, and/or increased afterload that may follow SFLP.

Echocardiographic data from our experience with severe TTTS suggest that TTTS results in hypertensive changes in the recipient twin that resolve with the arrest of the syndrome by SFLP. 12-14 Recipient fetal RV systolic pressures that were measured with echocardiography from valvular regurgitant jets consistently showed pressures in excess of 50-75mm Hg. 7; 44. In mid-gestation fetal hearts, this is an extraordinarily high pressure considering that normal fetal RV pressures are <25 mm Hg. 41. This finding often precedes advanced signs of TTTS, such as reversal of blood flow in the a wave of the ductus venosus, umbilical artery Doppler velocimetry changes, cardiac decompensation, or hydrops. We hypothesize that differential blood flow shifts in the monochorionic placenta results in high levels of placenta-derived vasoactive mediators that are shunted preferentially to the recipient twin that induce hypertensive cardiomyopathy. Interruption of these vascular communications by SFLP eliminates the hypertensive stress in the recipient twin that allows recovery of the recipient cardiac function, resolution of cardiac hypertrophy, valvular insufficiency, and even hydropic changes. 7; 12 In twins with TTTS who are treated by SFLP at our center, we have observed with echocardiography the postoperative resolution of these hypertensive changes in surviving recipient twins. 12 Consistent with the hypothesis that vasoactive mediators play an important role in TTTS, Bajoria et al l5 reported that endothelin-1, a potent vasoconstrictor, is 2.5-fold higher in the serum of recipient twins than in donor twins. Moreover, plasma endothelin-1 levels were significantly higher in the recipient twins with hydrops than in those with mild or no hydrops. 15 Autopsy results in recipient twins with TTTS that differentiated nephrosclerosis from hypertension are also consistent with this hypothesis. 42 Identifying vasoactive mediators that are responsible for TTTS would address a large gap in knowledge and potentially suggest new treatment approaches.

Nifedipine is a calcium channel blocker that antagonizes voltage-dependent L-type channels that result in vascular and extravascular smooth muscle relaxation. 26 It has a high oral absorption rate with low bioavailability (30-60%) because of substantial first-pass effect in the intestinal wall and the liver, whereby it is metabolized to less active metabolites by the oxidative pathway, mainly by the cytochrome P-450.43 It is highly protein bound (90-95%), and its metabolites are excreted mainly by the kidneys (70-80%). 26-29,44'45 Because of the aforementioned characteristics, nifedipine has a short half-life with large interindividual variability in its kinetics with the highly variable plasma concentrations after oral administration. 44 Peak serum concentrations are lower and the terminal elimination half-life (mean, 1.3 ±0.5 hours) is shorter during the third trimester, compared with levels in nonpregnant patients. 31 In addition, nifedipine is detected in samples of fetal cord blood and amniotic fluid at concentrations approximately 93% and 53% of those of simultaneously collected maternal vein samples, respectively. 31

This study was an observational case control cohort with treated and control subjects who were matched for gestational age and Cincinnati stage. The nifedipine-treated and control cohorts are from 2 different time periods during which both volume and experience with SFLP at our center increased. A possible alternative explanation for the survival benefit that was observed in recipients could be improvement in the technique over this timeframe. However, in both time periods, the same staging system, mapping protocol, and operative technique were used. It is important to note that members of our team with little experience with SFLP began operating during the time period that the nifedipine-treated cases were obtained argues against the improved recipient survival being due to improved surgical technique or experience. The retrospective nature of the study design, however, limits our ability to prove definitively that nifedipine is directly responsible for the survival benefit that was observed in the nifedipine-treated patients. A prospective randomized placebo-controlled trial will be necessary to prove definitively the beneficial effects of nifedipine on recipient cardiac function and survival in TTTS.

The apparent beneficial effect of nifedipine on survival suggests that, although the underlying pathophysiologic condition of TTTS still is understood incompletely, there is the potential for targeted medical therapy to improve outcomes. The underlying cause of TTTS remains unknown, and the positive findings in this study support greater efforts at defining the cause of TTTS to develop targeted medical therapies that might eliminate the need for invasive surgical interventions. (Crombleholme et al., 2010)

Fetoscopic Cord Coagulation / Radiofrequency Ablation

Some centers have taken the view that the most definitive approach to treating TTTS is selective reduction using fetoscopic cord ligation or coagulation. The rationale for this approach is that cord occlusion and sacrifice of one twin arrests the syndrome, prolongs the gestation, and maximizes the outcome for one twin. We have reserved this approach for instances where advanced TTTS cardiomyopathy has irretrievably compromised the recipient twin with no hope for salvage. In such cases, due to unequal sharing between the donor and recipient, the selective fetoscopic laser procedure may result in death of the donor twin from acute placental insufficiency within hours of the procedure and a recipient twin that dies from progressive TTTS cardiomyopathy. In this situation, fetoscopic cord coagulation may be the best option available.

Cord coagulation preserves the vascular communications between the donor twin and the placenta in the recipient twin's domain. In 16 of 17 such cases we have observed rebound fetal growth, restoration of amniotic fluid volume, and delivery of neurologically intact donor twin at a mean gestational age of 34 weeks. One survivor had a grade I intraventricular hemorrhage but is otherwise doing well.

SFLP vs. RFA for Stage IV TTTS

While selective reduction by RFA in stage IV TTTS may be an option, direct comparison of SFLP and RFA would suggest otherwise except in very specific cases. In a series of 50 patients with stage IV TTTS, in which 12 were treated with RFA and 38 were treated by SFLP, the overall fetal survival in the RFA treated cases was 50%. In contrast, those treated by SFLP had an overall fetal survival of 85%, with 100% having at least one survive and 70% having both twins survive. The recipient twin was invariably the hydropic twin due to TTTS cardiomyopathy. The recipient twin had on overall survival of 78% (donor survival was 93%). There were specific fetal echocardiographic parameters which predicted poor recipient survival. If the recipient twin had both pulmonic atresia and severe LV dysfunction the survival was only 20%. In the absence of pulmonic atresia and LV dysfunction survival of the recipient twin was 100%. If only one of these findings was present recipient survival was 88%.

We now reserve RFA in stage IV to highly select cases as outcomes with SFLP are so good.

Sequential Treatment

Our approach has been to offer sequential therapy to patients with early TTTS stages I, II or III in the absence of TTTS cardiomyopathy tailored to the needs of a given set of twins based on gestational age at presentation and evidence or progression of hemodynamic compromise based on Doppler velocimetry and echocardiographic changes.

In this approach, only those cases, in which less invasive approaches have failed, are offered the more invasive fetoscopic treatments. In patients who present later than 24 weeks gestation, we have favored amnioreduction or microseptostomy based on the more favorable prognosis in these patients.

In patients presenting prior to 24 weeks without advanced cardiac changes in the recipient, we have leaned toward observation (stage I or II) or a trial of amnioreduction. Patients presenting earlier in gestation tend to develop signs of hemodynamic progression of TTTS more rapidly.

For this reason, all pregnancies undergo close serial sonographic and echocardiographic surveillance for progression in cardiac and hemodynamic changes which would be an indication for selective fetoscopic laser surgery.

The Colorado Fetal Care Center's Dr. Crombleholme has 20 years of experience in the management and treatment of more than 900 cases of TTTS and is responsible for numerous research advances in our understanding and treatment of TTTS. Dr. Crombleholme was the principal investigators of the NIH sponsored Twin-Twin Transfusion Syndrome Trail comparing selective fetoscopic laser photocoagulation to amnioreduction, still the only study of TTTS ever funded by the NIH. The results of this trial demonstrated impact of TTTS cardiomyopathy on recipient survival. Dr. Crombleholme was the first to propose a staging system for TTTS cardiomyopathy. This staging system referred to as the Cincinnati modification of the Quintero staging system recognized the impact of TTTS cardiomyopathy on recipient twin survival.

Our research demonstrated the impact on TTTS cardiomyopathy of brain type atrial natriuretic factor produced by dilated cardiac chambers in response to stretch which has a highly potent diuretic effect which is largely responsible for the polyhydraminos in the recipient twin. Dr. Crombleholme pioneered the use of nifedipine, a calcium channel blocker, as an adjunctive treatment of TTTS cardiomyopathy. Dr. Crombleholme showed, in a prospective cohort study, that treatment of mothers with nifedipine prior to SFLP statistically significantly improves recipient twin survival.

The survival in TTTS treated by selective fetoscopic laser photocoagulation has progressively improved over the last decade. Overall, in 94% of all pregnancies treated, one or both twins survive, and in 85%, both twins survive. We have achieved these outcomes by reducing complication rates to the lowest ever reported with an incidence of persistent TTTS on twin anemia polycythemia sequence to < 1%. In addition, the use of nifedipine has significantly improved recipient survival. Lastly, we have shown that duration of the laser procedure has a direct impact on donor survival with laser time <5 minutes associated with 92% donor survival.

Dr. Crombleholme’s work in stage IV TTTS demonstrated that with few exceptions outstanding survival can be achieved with selective fetoscopic laser and that selective reduction with radiofrequency is rarely necessary.

While much attention has focused on the effect of treatment on survival in TTTS, the neurologic morbidity among survivors is often under-appreciated.

Due to the shared placental circulation, if death of one co-twin occurs there is an acute fall in blood pressure causing the placental resistance to fall. This drop in resistance across the placental vascular connections can result in a decrease in the cerebral perfusion pressure and ischemic injury in the brain of the surviving twin. Quintero et al. reported endoscopic evidence of feto-fetal hemorrhage from a recipient to donor twin within three hours of the spontaneous demise of the donor; these authors noted endoscopic and middle cerebral artery Doppler evidence of paradoxical anemia in the recipient and polycythemia in the donor.

Brain injury, however, can occur in TTTS even when both twins survive. In the recipient, when both twins survive, neurologic damage could be related to secondary to polycythemia and venous stasis. In the donor, neurologic injury may be due to anemia and hypotension.

The International Amnioreduction Registry tracked 223 women with TTTS diagnosed before 28 weeks gestation who were treated with serial aggressive amnioreduction. Of those infants who survived to 4 weeks of age and underwent clinically indicated cranial ultrasound, 24 percent of recipient (26 / 109 scanned) and 25 percent of donor twins (22/88 scanned) had abnormal findings.

Findings included severe intraventricular hemorrhage, ventricular dilation, cerebral echogenic foci, cerebral cysts among periventricular leukomalacia among other less common lesions.

Eighty infants died before reaching four weeks of age; how many of these would have had abnormal imaging if cranial ultrasonography had been performed is unknown. Among patients in the Twin-Twin Transfusion Syndrome Registry from Australia and New Zealand, most of whom had been treated with amnioreduction, the rate of abnormal cranial sonography was similar at 27.3%. The rate of periventricular leukomalacia in this group was 10. 8 percent, which is particularly important due to the association of this lesion with cerebral palsy. In another small series of patients treated with amnioreduction, the rate of abnormal neonatal cranial ultrasonography was as high as 58 percent.

Few studies report longer term neurodevelopmental outcome. Importantly, survivors who develop neurologic handicap and mental retardation do not always have abnormal neonatal ultrasonography.\Similarly, not all children with abnormal ultrasounds have clinically significant neurodevelopmental deficits. In one small study that followed TTTS survivors for a mean of 6.2 years (range 4-11 yrs), the incidence of cerebral palsy was 26 percent (5/19 infants) in the group treated by serial amnioreduction. All of these children had abnormal mental development in addition to motor deficits. Of note, three of the five children had normal neonatal head ultrasounds.

In the combined cohort of children whose mothers had been treated with amnioreduction or conservative treatment, 22 percent (5 / 23) of the children without cerebral palsy or abnormal mental development had mild speech delay and required special education.

One limitation to this, and other studies, is the lack of a comparable conservatively treated cohort group. Given the improved survival of TTTS babies with amnioreduction and other treatment modalities, however, it is unlikely that we will ever have such a cohort for comparison. Studying infants from pregnancies complicated by TTTS and treated with amnioreduction, Mari et al. detected a rate of cerebral palsy of 4.7 percent (2 of 42 infants) in those children who survived to more than 24 months of age.

One reason for the lower incidence of cerebral palsy than in the study by Lopriore et al. may be related to the latter study group having more severe disease given that all the patients were diagnosed before 28 weeks versus up to 33 weeks in Mari et al's study. Of note, Mari et al.'s study also detected 9 survivors with mild speech and / or motor delay.

Dickinson et al. studied the long term neurologic outcome of 52 children from 31 TTTS pregnancies who survived to more than 18 months; a majority of the mothers had been treated with amnioreduction. The comparison was a regional cohort of term and preterm infants, with the majority having been born very preterm. In addition, the TTTS babies were compared to matched singleton and twin control groups. The mean IQ of survivors with TTTS was significantly lower than the comparison cohort, mainly due to the decreased IQ of 13 points in those children born less than 33 weeks.

There was no difference in rate of cerebral palsy (5. 8% in TTTS vs. 4. 9% in very preterm twins vs. 3. 3% very preterm singletons) or behavioral tests in the TTTS survivors. This was a small study, however, and not sufficiently powered to demonstrate differences in cerebral palsy. Still, these researchers appropriately raise the issue that studies evaluating long term neurologic outcome in TTTS need to consider that most TTTS pregnancies are delivered very preterm as well as the fact that twins in general are more likely to be neurologically compromised with a baseline of significant neurodevelopmental abnormalities in 6% of monochorionic twins without TTTS.

Even fewer studies have examined the long term outcome of survivors of TTTS treated with intrauterine laser photocoagulation therapy. Banek et. al. reported that in 89 such children, 78 percent showed normal development at a median age of 22 months. Eleven percent had minor neurologic abnormalities including:

  • Strabismus
  • Mildly delayed motor development
  • Mildly abnormal speech

The remaining 11 percent suffered significant neurologic deficiencies including:

  • Cerebral palsy
  • Hemiparesis
  • Spastic quadriplegia

Of note, significantly more children in the neurologically impaired groups were born very preterm. Two of the most severely affected group had abnormal brain scans before laser treatment. The findings of this study are consistent with those of Sutcliffe et al. who reported a cerebral palsy rate of 9 percent in children after in utero treatment with laser therapy for TTTS.


The Eurofoetus Trial (40), the first prospective randomized clinical trial published comparing serial amnioreduction to laser photocoagulation for the treatment of TTTS, suggests that laser therapy improves survival and neurologic outcome at six months of life. However, questions still remain in regard to which patients will benefit most from laser as well as how amnioreduction and laser therapy affect short term and long term cardiac and neurodevelopmental outcomes.

Crombleholme et al. conducted a National Institutes of Health (NIH) sponsored multicenter prospective randomized controlled trial comparing aggressive amnioreduction with selective fetoscopic laser photocoagulation for severe TTTS presenting prior to 22 weeks gestation. Only patients who failed to respond to initial amnioreduction qualified for the NIH sponsored trial.

Entry into the trial was closed after 42 patients were randomized, but follow-up of all patients treated in the trial will continue until their neurodevelopment assessment at 18 to 22 months in the NICHD Neonatal Network. The survival data, blinded sonographic data, echocardiographic data, MRI data, placental pathology, and neonatal co-morbidity data of all patients randomized in the trial and in the observation arm of the study are currently being analyzed.

A thoughtful approach to the management of TTTS requires consideration of every aspect of the presentation including gestational age, stage, Doppler findings, echocardiographic findings, concomitant placental insufficiency, and maternal risk factors. Until we have an effective medical therapy for TTTS, a judicious application of invasive procedures should be employed to optimize risk: benefit ratios for the mother and fetuses.

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Our top-ranked, internationally known surgeons at the Colorado Fetal Care Center treat Twin-to-Twin Transfusion Syndrome (TTTS) and other fetal abnormalities. If you or someone close to you is experiencing TTTS, please contact us for an appointment or to schedule a tour of our facility.

A family's story of surviving TTTS

Hear about the Millers, who through the Fetal Health Foundation, found Dr. Crombleholme and his team of experts at the Colorado Fetal Care Center after learning that their unborn twins had TTTS. Learn how this trying time in their lives now holds peace and gratefulness.


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