The twin-to-twin transfusion syndrome (TTTS) is a complication of multiple gestation resulting from imbalanced blood flow through vascular communications in the placenta (chorangiopagus), such that one twin is compromised and the other is favored. The prognosis is poor, with a perinatal mortality rate ranging from 60% to 100% for both twins (Rausen et al., 1965; Cheschier and Seeds, 1988; Gonsoulin et al., 1990).

The earliest description of TTTS may have been in the book of Genesis. At the birth of Esau and Jacob it was recorded that “the first one came out red,” possibly describing the birth of a polycythemic twin. In 1752, William Smellie reported the injection of the umbilical artery of one twin with the injection material flowing out of the vessel of the co-twin.

Research in the area of vascular anastomoses in twin placenta in the late 1800s was dominated by the German obstetrician Friedreich Schatz, who described four types of vascular connections within monochorionic placentas:

1. 
   

   Superficial connections between capillaries.

   
   
2. 
   

   Superficial arterial connections between large vessels.

   
   
3. 
   

   Superficial venous connections between large vessels.

   
   
4. 
   

   Vascular communications between capillaries in the villi.

He described three circulatory systems in monochorionic twins. The first two were the circulations in either twin. The third circulation consisted of the arteriovenous communications bridging the two fetal circulations below the placental surface (Schatz, 1882).

Schatz proposed that when superficial artery-to-artery and vein-to-vein anastomoses are absent or insufficient, imbalances may occur in the common circulation of the twins. Such imbalances favor the transfer of blood from one twin to the other and result in TTTS. A study demonstrating fewer anastomoses from placentas complicated by TTTS (Bajoria et al., 1995) confirms Schatz’s observations from the late 1800s. Ten placentas from pregnancies with evidence of midtrimester TTTS diagnosed using ultrasound criteria were compared with 10 placentas from pregnancies without TTTS. Placentas from pregnancies with TTTS had significantly fewer anastomoses than did those without TTTS, both overall and for each of the different types (arterioarterial, venovenous, and arteriovenous). Whereas multiple anastomoses were present in all controls, only one TTTS placenta had more than a single communication. Anastomoses in the TTTS group were more likely to be of the deep than the superficial type.

Because of the putative major role of intertwin anastomoses, most investigations of TTTS have been directed toward study of the monochorionic diamniotic placental vasculature. Studies generally have identified a paucity of anastomoses as a prominent risk factor in the development of TTTS. Paucity, especially of deep anastomoses, leads to fewer chances for volumetric balance in cross-circulation between the twins. Larger numbers of superficial chorionic anastomoses, particularly arterioarterial (A-A) connections, appear to confer relative protection against the development, early onset, or severity of TTTS (De Lia et al., 2000; Umur et al., 2002a; De Paepe et al., 2005; Harkness and Crombleholme, 2005; Lewi et al., 2007). However, the “protective effect” of these A-A anastomoses remains somewhat controversial. Venovenous (V-V) connections comprise a lower percentage of anastomotic types found in monochorionic diamniotic gestations and have been associated with poorer perinatal outcome. V-V anastomoses are seen in 20% of monochorionic diamniotic placentas, A-A in 75%, and A-V in 70% byclinical and pathologic studies, but fetoscopic studies have shown that 95% of anastomoses are A-V (De Lia et al., 2000; Crombleholme et al., 2007). However, some investigators have proposed that V-V anastomoses may provide compensatory reversal of blood flow in some situations (De Lia, 2000). Presumably, as the recipient’s central venous pressure rises with hypervolemia and ensuing congestive failure, the V-V anastomoses may be “protective” to both twins by helping to alleviate right ventricular failure in the recipient and theoretically shunting blood back to the venous system of the donor. The relatively fewer numbers of V-V connections, in addition to their anatomy and lower pressure differential, may be determinants of how effectively they contribute to balancing intertwin blood flow.

Some researchers’ observations that the average numbers of superficial vascular connections are not significantly different between gestations involving severe TTTS and those that do not (Bermudez et al., 2002) and the fact that 80% to 90% of monochorionic diamniotic twins do not develop TTTS has led other investigators to propose that more than quantitative differences in the number of anastomoses is involved in the pathogenesis TTTS. Recent evidence suggests that vascular diameter and resistance and the pattern of chorionic plate vascular branching are important factors. Umur et al. (2002a,b) using a complex mathematical computer model, determined that, for a given radius, an A-A anastomosis has lower resistance than the equally sized afferent artery of an A-V anastomosis, which might explain the apparent protective effect of A-A anastomoses noted in most studies of TTTS. By their calculations, blood flow could be balanced more efficaciously through an A-A anastomosis than through oppositely directed A-V anastomoses, even though the pressure gradient in the A-V anastomoses was greater.

De Paepe et al. (2005) studied the chorionic plate branching pattern in monochorionic diamniotic placentas from gestations without TTTS and those affected by severe TTTS. They found that gestations involving severe TTTS were more likely to exhibit magistral pattern (a chorionic vascular pattern composed of relatively large caliber, sparsely branching vessels that extended from the cord insertion site to the placental periphery without significant diminution in diameter), or a mixed magistral and diffuse pattern than unaffected gestations (60% vs. 44%). The presence of a magistral pattern, even when mixed with the more favorable disperse pattern, was also associated with higher incidences of other placental anatomic features implicated in the development of TTTS, such as unequal distribution of vascular territory and marginal or velamentous cord insertions. In addition, donor twins were more than twice as likely to have the magistral or mixed pattern as recipients, and when one or both twins had the magistral or mixed pattern, the average number of intertwin anastomoses was fewer. These investigators suggested that the predominance of magistral and mixed patterns in the donor twins’ placentas may be related to the observations that magistral patterns in singleton placentas are associated with absent enddiastolic blood flow (AEDF) in the umbilical arteries (UAs). AEDF has been attributed to the effects of a smaller peripheral vascular tree that results in increased vascular resistance to forward flow from the UAs. The low end-diastolic flow in the donor’s UAs combined with the magistral/mixed pattern might result in preferential routing of blood flow through anastomoses to the recipient twin. Thus, evidence supplied by the various placental structural studies of TTTS indicates vascular resistance, cross-sectional area, and other hemodynamic factors are contributing elements in the development, timing of clinical onset, and severity of TTTS (Luks et al., 2005).

Unequal sharing of the placental disc is an additional risk factor for the development of TTTS (Benirschke et al., 2006; Lewi et al., 2007). However, when and how disk inequality develops is unclear. The early developing chorionic villous tree may connect preferentially to the vasculature of the umbilical cord of one twin over that of the other. With unequal division of the inner cell mass, one embryo may develop a larger heart and, thereby, greater stroke volume and cardiac output such that its perfusion of the developing villous tree is initially more robust (Benirschke et al., 2006). However, others have proposed that unequal sharing may reflect abnormalities of placentation. Not all twin pairs that have TTTS exhibit significant growth discordance, and there is evidence that abnormalities of placentation may be relatively more responsible for the growth discordance in TTTS than imbalances in intertwin transfusion (Wee et al., 2006). Approximately 20% of cases of TTTS have concomitant evidence of placental insufficiency that usually, but not always, affects the donor twin (Habli et al., 2008). The combination of placentation anomalies, flow inequalities, and fetal response may determine whether the donor’s placental territory appears grossly pale and bulky [with edematous large villi containing increased Hofbauer (chorionic villous macrophage) cells and nucleated fetal erythrocytes characteristic of fetal anemia] or whether it is pale and atrophicappearing with small villi (Kraus et al., 2005; Faye-Petersen et al., 2006; Kaplan, 2007). Conversely, the recipient’s parenchymal territory usually is deep red-brown and firm due to villous congestion, but it also may show microscopic villous edema if the fetus is in congestive failure.

Marginal and velamentous cord insertions and single UA are associated with increased risks of the development and severity of TTTS (Fries et al., 1993; De Paepe et al., 2005; Benirschke et al., 2006; Kaplan, 2007). Of note, although diamniotic monochorionic twins comprise 20% of twin gestations, they have significantly increased rates of cord anomalies over diamniotic dichorionic twins, with more than 50% of marginal cord insertions, more than 40% of velamentous cord insertions, and nearly 50% of all single UA cases occurring in monochorionic diamniotic twins (Redline et al., 2001). Diamniotic monochorionic twins, therefore, are at constitutively increased risks for the underlying morbidity and mortality associated with cord compression, cord accident with thrombosis, and vessel rupture. Such cord events could compound any underlying risks ofchorangiopagus, especially for the donor twin. Donor twins are more likely to have velamentous cord insertion than are recipients (Mari et al., 2000).

The asymmetric, bidirectional intertwin exchange of blood and its biochemical components results in hemodynamic, osmotic, and physiologic changes in the fetuses (Jain and Fisk, 2004; Harkness and Crombleholme, 2005; Luks et al., 2005; Benirschke et al., 2006). Hypovolemia and decreased renal blood flow in the donor may cause a number of renal structural and functional aberrations, especially in severe TTTS, including renal tubular degeneration and cellular apoptosis, loss of glomeruli or reduction in tubular number, and maldevelopmental progression to renal dysgenesis (Kilby et al., 2001; De Paepe et al., 2003). Renal hypoperfusion also has been linked to activation of the renin-angiotensin system (RAS) (Mahieu-Caputo et al., 2000; Kilby et al., 2001; Mahieu-Caputo et al., 2001) and elevated antidiuretic hormone concentrations (Bajoria et al., 2004) in the donor. Donors have hyperplasia of juxtaglomerular apparatuses, with increased numbers of renin-secreting cells (Kilby et al., 2001) and up-regulation of renin synthesis (Mahieu-Caputo et al., 2000), which are presumed to represent adaptive responses to restore euvolemia. However, in severe TTTS, activation of the RAS and associated elevations in angiotensin II (AT II) likely result in AT II-mediated fetal vasoconstriction that further compromises renal blood flow, leading to worsening oliguria and oligohydramnios. Increased fetal adrenal production of aldosterone may play a contributing role (Mahieu-Caputo et al., 2000; Kilby et al., 2001; Mahieu-Caputo et al., 2001; Bajoria et al., 2004). Bajoria et al. (2004) recently found that donors’ plasma and amniotic fluid concentrations of vasopressin were threefold higher than those of their co-twin recipients (monochorionic diamniotic twins that did not have TTTS had higher concentrations than the recipients in TTTS, but they were not discrepant or as elevated as the donors in TTTS). Thus, good evidence suggests that the oligohydramnios of the donor twin is a consequence of poor renal perfusion due to net hypovolemia, but it is exacerbated by vasoconstriction, mediated by AT II/vasopressin. Fetal vasoconstriction also may reduce placental blood flow to the villous tree, which may contribute to growth restriction in the donor (Mahieu-Caputo et al., 2000, 2001; Kilby et al., 2001).

In severe cases of TTTS, hypervolemic recipients have renomegaly and glomerulomegaly consistent with increased renal blood flow, and immunohistochemical studies have revealed they have downregulation of the RAS, with markedly reduced numbers of renin-secreting cells and renin synthesis (Mahieu-Caputo et al., 2000, 2001; Kilby et al., 2001). However, they have paradoxically high concentrations of renin and aldosterone, and the cardiomegaly, cardiomyopathy, hypertension, and nephrosclerosis seen in recipients in TTTS are insufficiently explained by hypervolemia alone. Such observations are supportive evidence for transfer of these and possibly other vasoactive effectors from the donor to the recipient across placental anastomoses. The hemorrhagic necrosis and microangiopathic lesions seen in kidneys from recipients in severe TTTS also may be related to transanastomotic passage of hormones from the donor (Mahieu-Caputo et al., 2001, 2005). Low concentrations of antidiuretic hormone in the recipient, together with elevated renin concentrations secreted by the donor, are likely responsible for worsening hypervolemia and polyuria/polyhydramnios in recipients. Maternal sequelae of fetal elevations in vasoactive substances have been appreciated recently. Elevated fetal renin-AT II values have been associated with maternal pseudoprimary hyperal-dosteronism (Gussi et al., 2007), and it is possible that these contribute to changes in maternal perfusion of the placental bed.

In addition to anastomotic transfer of vasoactive mediators, increased cardiac synthesis and secretion of natriuretic peptides (NPs) have been linked to the progression of TTTS. NPs are a family of biochemical mediators that normally regulate blood pressure and body fluid homeostasis through their diuretic, natriuretic, and vasodilatory effects as well exerting antiproliferative effects on cardiovascular/mesenchymal tissue. Exploration of their role in the pathogenesis of adult cardiac hypertrophy and cardiomyopathy has led to greater appreciation of their importance in normal embryofetal development and their role in cardiomyopathy in the recipient twin in TTTS. In the fetus, in contrast to the adult, both atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) hormones are normally at high circulating concentrations and are expressed at high concentrations in the ventricles (in the normal adult, they are expressed at low concentrations in cardiac atria and ventricles, respectively). Their release is stimulated primarily by increased myocardial stretch and volume overload, hyperosmolality, and hypoxia, and vasoconstrictors, such as AT II, vasopressin, and endothelin-1 (ET-1), have been shown to result in their increased expression and secretion. ANPs and BNPs appear to be integral to embryonic fetal salt and water and blood pressure regulation, and the peptide system is likely functional by midgestation. ANP and BNP also appear to be important mediators of cardiogenesis because of their inhibitory effects on myocardial and fibroblast cell proliferation. Their effects on fetal aldosterone concentrations are unknown, but they suppress aldosterone synthesis in the adult. A third NP, c-type natriuretic peptide (CNP), which is found in adult genitourinary, pituitary, and brain tissues, is not produced in any significant quantity in the fetal or adult heart, although it is secreted by the placenta. Placental production of NPs (ANP, BNP, CNP) affects vasorelaxation in the fetoplacental vasculature and likely helps regulate blood supply to and within the fetus.

Bajoria et al. (2002, 2003) demonstrated that recipient twins in TTTS have higher concentrations of ANP, BNP, and ET-1 than their co-twin donors or monochorionic diamniotic twins without TTTS and that high concentrations of BNP and ET-1 are particularly correlated with cardiac dysfunction in the recipient. They suggested that these compounds might be used as early markers of cardiac compromise. It is plausible that the immaturity of the fetal kidney and its inability to concentrate urine may be exacerbated by the vasodilatory and diuretic effects of BNP and ANP released due to hyper-volemia and contribute to polyuria/polyhydramnios or be compounded by BNP stimulation due to AT II transferred from the donor. Increased ANP concentrations in blood and amniotic fluid have been detected in recipients in TTTS, greater than donor twin’s and uncomplicated monochorionic diamniotic twin pair’s values. Increases in ANP also are related directly to increases in amniotic fluid volumes, and markedly increased immunostaining for ANP localizes predominantly to the heart and cytoplasm of the distal convoluted tubules of the kidneys of recipients when compared with measurements for donor twins. These data are supportive evidence that polyhydramnios in the recipient twin occurs as a consequence of ANP-mediated increases in fetal urine output due to ANP expression in both cardiac and renal tissues (Bajoria et al., 2001).

Cardiac hypertrophy with cardiac dilatation is seen in recipients in TTTS and likely is due to the increased cardiac preload and increased afterload pressures due to hypertension (Mahieu-Caputo et al., 2001, 2003). Of note, ventricular hypertrophy predominates and dilatation is comparatively “mild,” with right ventricular compromise preceding and generally exceeding that of the left ventricle (Harkness and Crombleholme, 2005). Although the right ventricle is the primary “workhorse” of the fetal heart, and fetal myocardium can proliferate, other developmental factors likely contribute to the myocardial mural thickening detected by ultrasonography. Fetal myocardium is “stiffer” than the adult heart. The fetal myocardium has a greater percentage of noncontractile elements (60% vs. 30% in the mature heart) and relatively delayed removal of calcium from troponin C, and the ventricles have a shorter phase of early passive diastolic filling and a greater reliance on atrial contraction. Fetal lamb studies have shown that after 4 to 5 mm Hg, further atrial preload does not result in increased stoke volume. Thus, the fetal heart is inherently and mechanically less efficient, is less able to increase stroke volume, and displays impaired relaxation (Szwast and Rychik, 2005). These effects may represent, in part, disruption of the NP system, which has been shown to be NP receptor-dependent in murine models. NP receptor-deficient, Nprl–/– knockout mice develop hypertension, cardiac hypertrophy, and fibrosis. The absence of the receptor effectively inhibits vasorelaxation despite elevated concentrations of BNP and ANP. Moreover, cardiac hypertrophy can result independently of the presence of hypertension because the lack of receptor does not permit inhibition of myocardial proliferation/enlargement and fibroplasia.

Recipient twins are at increased risk for right ventricular outflow tract obstruction and pulmonary valvar steno-sis/atresia with intact ventricular septum (Harkness and Crombleholme, 2005). The progressive hypertrophy, reduced systolic function, and tricuspid valvar insufficiency lead to progressive decline in flow across the pulmonary valve. In a case in which the infant underwent surgical repair, the trileaflet semilunar valvar anatomy was identified as normal except for adhesions of the coapted leaflets. Thus, the pulmonary valvar stenosis/atresia in recipient twins seems to represent a unique form of “acquired congenital heart disease” and not a primary malformation (Harkness and Crombleholme, 2005). ANP/BNP signaling interruption may play a significant role in the generation of cardiac hypertrophy and dysfunction (Cameron and Ellmers, 2003). The right and left ventricular myocardium have embryologic differences, and the number of NP receptors in the right ventricle may be inherently lower; once proliferation and hypertrophy ensue, the right ventricle may become progressively more vulnerable to the effects of preload, afterload, and pressors.

Although cardiac dysfunction is more common and more dramatic in recipients, decreased cardiac performance and injury also may occur in donor twins in TTTS (Harkness and Crombleholme, 2005; Luks et al., 2005). Protracted increase in cardiac demands and energy expenditure, due to continued transfusion of the co-twin, and hypoxemia and acidemia, due to the anemia and probable shrinking efficiency of placental function, contribute to reduced cardiac function and growth restriction in the donor (Luks et al., 2005). Umbilical arterial end-diastolic forward (AEDF) blood flow diminishes to become absent (Mahieu-Caputo et al., 2003; Umur et al., 2003; Jain and Fisk, 2004; Luks et al., 2005; Wee et al., 2006). Hydrops from high-output cardiac failure can ensue in the donor due to loss of oncotic pressure from chronic transfusion (Luks et al., 2005) and hypoproteinemia due to passive hepatic congestion and reduced hepatic synthesis that reflects reduced blood delivery to the liver (due to splanchnic vasoconstriction and relative preservation of blood shunting through the ductus venosus with effective bypass of the liver) and placental insufficiency with reduced nutritional supply.

Vascular communications occur in all monochorionic but rarely in dichorionic placentas. TTTS is therefore almost exclusively found in monochorionic twins. TTTS is estimated to occur in 5% to 15% of monochorionic twin pregnancies (Rausen et al., 1965; Benirschke and Kim, 1973). Lage et al. (1989) described a case of TTTS resulting from vascular anastomoses within a fused dichorionic twin placenta. Robertson and Neer (1983) reported two cases of TTTS in dichorionic pregnancies.

The true incidence of TTTS is difficult to ascertain. TTTS may occur very early during the second trimester, with loss of both fetuses; in midgestation or at term. It is of most concern to the perinatologist when it occurs in midsecond trimester, when the syndrome results in polyhydramnios, often with spontaneous rupture of membranes, or in spontaneous labor that leads to premature delivery. Because TTTS can have such a wide spectrum of clinical presentation, in many cases the diagnosis may go unrecognized.

Wittmann et al. (1981) and Brennan et al. (1982) have suggested the sonographic criteria for the diagnosis of TTTS, including: (1) significant size disparity in fetuses of the same sex, (2) disparity in size between two amniotic sacs, (3) disparity in size of the umbilical cords, (4) single placenta, and (5) evidence of hydrops in either fetus or findings of congestive cardiac failure in the recipient. However, discordant growth is a common complication of twin pregnancies, and causes other than TTTS exist for discordant amniotic fluid volumes. The criterion of a birth weight difference of greater than 20% for the diagnosis of TTTS is based on the belief that the donor twin becomes growth restricted as a result of anemia and hypoalbuminemia. However, Sherer et al. (1994) reported a case of acute intrapartum TTTS so severe as to cause the death of both twins. In this report, the birth weights of the infants differed by only 2%.

In some cases, the discordance in amniotic fluid volume is so great that the amnion adheres to the smaller baby, so that it appears “stuck” to the wall of the uterus (Figure 119-1). In this situation it may be extremely difficult to visualize the dividing membrane between the twins. The “stuck twin” phenomenon is not pathognomonic for TTTS; it may also result from structural fetal anomalies, congenital infe tion, chromosomal abnormalities, or ruptured membran (Patten et al., 1989). In contrast, the co-twin moves freely in normal or increased amniotic fluid volume (see Figure 119-1 On ultrasound examination, signs of hydrops fetalis are occasionally found in the recipient (Brennan et al., 1982), rare in the donor (Rausen et al., 1965), and exceptionally in bol (McCafee et al., 1970).

In addition to measuring biometry and amniotic flu volume, Doppler velocimetry can be used to confirm the d agnosis of TTTS. Nonetheless, studies have provided coflicting results. Farmakides et al. (1985) reported two cases in which UA waveforms of the twins were discordant an concluded that simultaneous observation of high- and low resistance UA systolic/diastolic (S/D) ratios was suggesti of TTTS. Meanwhile, Giles et al. (1985) found no differem in interpair S/D ratios in eight cases where the diagnosis was documented or strongly suspected. Pretorius et al. (1988) also reported eight cases of TTTS and found no consistent patter in Doppler studies. Five of the eight pregnancies resulted in fetal or neonatal death of both twins. In these cases of perintal loss, one or both of the twins had either absent or reverse diastolic flow. The authors concluded that, while abnorm Doppler studies are not helpful in identifying the donor from the recipient twin, it invariably predicts a poor outcome. Data from the Australian and New Zealand TTTS Registry support these observations (Dickinson and Evans, 2000). Ishimats et al. (1992) were also unable to identify any distinctive finings in the UA blood flow velocity waveforms in patients with TTTS. However, the presence of cardiomegaly in five recipiei twins, with tricuspid regurgitation and a biphasic umbilical vein waveform in three others, led these authors to suggest that these findings may be more diagnostic than UA Doppler velocimetry and representative of the hemodynamic changes that occurring in TTTS. It is interesting to note that AA anastomoses can be identified using Doppler ultrasound as early as the first trimester, and absence of these anastomoses has been found to be associated with an increased risk for TTTS (Jain and Fisk, 2004).

A staging system for TTTS has been developed by Quintero et al. (1999) for the purpose of categorizing disease severity and standardizing comparison of different treatment results. In Stage I there is oligohydramnios, but the donor twin bladder is visible; in Stage II the bladder of the donor twin is no longer visible; in Stage III abnormal Doppler studies are evident (i.e., absent/reversed end-diastolic velocity in the UA, reversed flow in the ductus venosus, or pulsatile flow in the umbilical vein); Stage IV is complicated by hydrops; and in Stage V one or both fetuses have died.

Taylor et al. (2000) applied the Quintero staging system to a population treated with serial amnioreduction (AR), septostomy, and selective reduction alone or in combination and found no significant influence of staging at presentation on survival in their conservatively treated group. Survival was significantly poorer when stage increased rather than decreased. These authors concluded that the Quintero staging system should be used cautiously for determining prognosis at the time of diagnosis, suggesting that it 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 (overall number of fetuses surviving of the total number of fetuses treated) and double survival (number of pregnancies with two survivors), but not survival of any twin (number of pregnancies with survival of one or both twins) (Taylor et al., 2002). Duncombe et al. (2003) also showed a correlation of Quintero stage at initial presentation and perinatal survival.

The Quintero staging system, although useful in describing the progression of TTTS along the clinical spectrum of severity, has potential limitations in guiding therapy. For 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 who have Stage II presentation usually are believed to be in the early stages of the disease. The use of echocardiography to identify findings of recipient TTTS cardiomyopathy can confirm the diagnosis in Stage I cases when it may be in doubt. In addition, echocardiographic findings can alert the clinician to more advanced disease than the Quintero Stage suggests. The largest group of patients tends to fall into Stage III, but this stage comprises a very broad spectrum of severity. At one end are patients whose only hemodynamic derangement is abnormal UA Doppler velocimetry, and at the other end of the spectrum are patients in whom the recipient twin has severe, end-stage, twin–twin cardiomyopathy. These latter patients may be premorbid but without the development of hydrops (Stage IV disease). The Quintero staging system is heavily weighted toward findings in the donor twin. The absence of a visible bladder in the donor upstages the case to Stage II. The critical Doppler abnormalities that are required for Stage III almost always are observed in the donor twin. Critical Doppler waveform abnormalities in the recipient twin are rare until end-stage TTTS has been reached. In addition, there is no assessment of the TTTS cardiomyopathy, which only occurs in the recipient and has a profound impact on survival of the recipient (Harkness and Crombleholme, 2005; Michelfelder et al., 2007; Habli et al., 2008).

The Fetal Care Center of Cincinnati has used fetal echocardiographic assessment of the recipient twin to stage patients (Table 119-1). This is in keeping with the view that TTTS is a fundamentally hemodynamic derangement. Fetal echocardiography can distinguish degrees of severity among the broad spectrum of severity in Stage III TTTS and identify sicker patients in Stages I and II. Echocardiographic features include the presence and severity of atrioventricular valvar incompetence, ventricular wall thickening, and ventricular function, as assessed by the Tei Myocardial performance index (Barrea et al., 2005; Ichizuka et al., 2005). In recent reviews of experience with the Cincinnati staging system, 20% to 55% of Quintero Stage I and II patients were upstaged to Stage III disease based on echocardiographic findings (Michelfelder et al., 2007; Habli et al., 2008). The impact of TTTS cardiomyopathy on recipient twin survival had been demonstrated by Shah et al. (2008) in patients treated by fetoscopic laser who were stratified by cardiovascular profile score and in the National Institutes of Health TTTS trial in which echocardiographic findings of TTTS were the single most important predictor of adverse recipient survival (Crombleholme et al., 2007; Shah et al., 2008). The upstaging of patients from Stage II to Stage III may influence counseling about treatment options. These echocardiographic features also are used to assess response to therapy. If a patient is treated initially with AR or microseptostomy, fetal echocardiography can be used to assess progression of TTTS despite therapy and as an indication for selective fetoscopic laser photocoagulation (Crombleholme et al., 2006, 2007; Habli et al., 2008).

Intrauterine cardiac dysfunction and hemodynamic derangements lead to ischemic brain lesions, including white matter infarction and leukoencephalopathy, intraventricular hemorrhage, hydranencephaly, and porencephaly, which can be detected by prenatal ultrasonography (Denbow et al., 1998; De Lia et al., 2000; Mari et al., 2000; Taylor et al., 2000; Kline-Fath et al., 2007). Up to 8% of TTTS cases have evidence of CNS injury on fetal magnetic resonance imaging (MRI) at the time of presentation prior to treatment. Such CNS findings range from ischemic or hemorrhagic changes in the brain to marked dilation of the cerebral venous sinuses due to central venous hypertension. The latter has been shown to correlate with worse survival when detected in TTTS (Kline-Fath et al., 2007). When these lesions are seen in surviving twins of instances of co-twin death [66% of cases with intrauterine death involve demise of the donor twin (Weisz et al., 2004)], they have been attributed to sudden acute TTTS (De Lia et al., 2000; Kraus et al., 2005) through arterioarterial (A-A) anastomoses (De Lia et al., 2000). Due to the sharedplacental circulation, if one co-twin dies, there is an acute fall in blood pressure that causes placental resistance to decrease. This decrease in resistance across the placental vascular connections can result in reduced cerebral perfusion pressure and ischemic injury in the brain of the surviving twin. Quintero et al. (2002) reported endo-scopic evidence of fetofetal hemorrhage from a recipient to donor twin within 3 hours of the spontaneous demise of the donor, noting endoscopic and middle cerebral artery Doppler evidence of paradoxic anemia in the recipient and erythrocythemia in the donor. TTTS can result in significant neurologic damage, with 5% to 27% of surviving twins having evidence of CNS sequelae on postnatal MRI or ultrasonography (De Lia et al., 1995; Ville et al., 1995; Hecher et al., 1999; Senat et al., 2004; Kraus et al., 2005). Brain injury, however, can occur in TTTS even when both twins survive. When both twins survive, neurologic damage in the recipient may be related to secondary polycythemia and venous stasis. In the donor, neurologic injury may be due to anemia and hypotension.