The twin-to-twin transfusion syndrome (TTTS) is a complication of monochorionic multiple gestations resulting from 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.
TTTS is almost exclusively found in monochorionic twins and is estimated to occur in 5% to 15% of monochorionic twin pregnancies.
Sonographic criteria for the diagnosis of TTTS include: (1) like sex, (2) monochorionic twins, (3) polyhydramnios in one sac, oligohydramnios in the other sac with or without characteristic Doppler or echocardiographic changes.
Expectant management is not recommended due to poor perinatal outcomes associated with the disorder.
Treatment depends on the gestational age and severity at diagnosis.
Current treatment options for severe TTTS include: (1) serial reduction amniocentesis, (2) amniotic septostomy, (3) laser ablation of the anastomoses, and (4) intrafetal radiofrequency ablation.
Laser ablation appears to be a promising treatment for severe TTTS diagnosed in the midtrimester. Nonetheless, further studies are still needed to assess long-term pediatric outcome.
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:
Superficial connections between capillaries.
Superficial arterial connections between large vessels.
Superficial venous connections between large vessels.
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).
Prenatal sonographic image demonstrating a “stuck” twin in the upper left section of the image and the co-twin in a sac with polyhydramnios.
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).
Table 119-1Cincinnati Modification of the Quintero Staging System and the Sequence of Progressive Events in Untreated TTTS ||Download (.pdf) Table 119-1 Cincinnati Modification of the Quintero Staging System and the Sequence of Progressive Events in Untreated TTTS
|Stage ||Donor ||Recipient ||Recipient Cardiomyopathy |
|I ||Oligohydramnios (DVP <2 cm) ||Polyhydramnios (DVP >8 cm) ||No |
|II ||Absent bladder ||Bladder seen ||No |
|III ||Abnormal Doppler finding ||Abnormal Doppler finding ||None |
|IIIa || || ||Mild* |
|IIIb || || ||Moderate* |
|IIIc || || ||Severe* |
|IV ||Hydrops ||Hydrops || |
|V ||Death ||Death || |
|Variables/cardiomyopathy ||Mild ||Moderate ||Severe |
|AV regurgitation ||Mild ||Moderate ||Severe |
|RV/LV thickness ||>+2 Z-score ||>+3 Z-score ||>+4 Z-score |
|MPI ||>+2 Z-score ||>+3 Z-score ||Severe biventricular dysfunction |
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.
Multiorgan ischemic sequelae also are seen. Renal failure occurs in 48% of survivors compared with 14% of agedmatched controls (Jain and Fisk, 2004). Renal cortical necrosis, intestinal atresia, and cutis aplasia may be seen in one or both twins (Denbow et al., 1998; Luks et al., 2001; Carr et al., 2004). Limb necrosis and other ischemic lesions and hemolytic jaundice in the surviving recipient twin may be related to hyperviscosity (erythrocythemia) (Carr et al., 2004) or thromboembolic phenomena due to placental chorangiopagus vessels (Margono et al., 1992).
Diamniotic monochorionic twins are at increased risk for structural cardiac anomalies in at least one twin; 7% of monochorionic diamniotic twins have congenital heart defects (CHD) (Manning and Archer, 2006) compared with the overall prevalence of 0.5% seen in neonates (Bahtiyar et al., 2007). Bahtiyar et al. (2007), in their multistudy review of the prevalence of CHD in monochorionic diamniotic twins, found an overall ninefold increased risk for CHD over singletons, a 15- to 23-fold higher risk of CHD with TTTS over that of singletons, and a 2.78 times more frequent occurrence of CHD in the setting of TTTS compared with no TTTS. These overall and relatively increased risks are probably related to the greater frequency of abnormalities of placentation and the umbilical cord in monochorionic diamniotic gestations and their relative predominance in TTTS, respectively. However, the etiopathogenesis of cardiovascular malformations is poorly understood, even in singletons. Thus, the increased prevalence of cardiac malformations in monochorionic diamniotic twins, and especially in those pairs affected by TTTS, probably represents a complex interaction among many variables such as fetal blood flow fluctuations, vascular endothelial growth factors (VEGFs) and other mediators, the process of twinning itself, unequal sharing of the placenta, and inherent genetic factors.
The most common defects in monochorionic diamniotic twins are ventricular septal defect (VSD), pulmonary stenosis, and atrial septal defect. The prevalence of VSDs in TTTS, although higher, is not remarkably different from that in uncomplicated monochorionic diamniotic gestations (0.024 and 0.019, respectively). The detection of VSDs may represent sites of ischemic necrosis or excessive natriuretic proteins during early embryonic life. However, the membranous septum is a complex structure that has numerous embryologic components effecting its closure and VSDs, together with patent ductus arteriosus, are the most common cardiac defects in infancy. The pathogenesis of VSD is unclear, but its mildly increased incidence in TTTS infants may be related to a combination of factors, including its relatively greater general frequency and the increased risk of ischemia in TTTS due to abnormal placentation or ischemia due to hypovolemia. Bahtiyar et al. (2007) postulated that because recent studies indicate that the cause of CHD is partly due to aberrant angiogenic factors such as VEGF, the increased prevalence of CHD in TTTS may represent the deleterious effects of angiogenic factors. VEGF is upregulated in ischemia, and Dor et al. (2001) found that VEGF is specifically upregulated during normal heart development in the atrioventricular field of the heart, soon after the onset of endocardial cushion formation. Premature induction of myocardial VEGF prevents formation of endocardial cushions in animal models.
The prevalence of pulmonary stenosis is fourfold greater in gestations involving TTTS compared with those not involving TTTS (0.028 vs. 0.007), and atrial septal defects (0.024) are seen only in twins who have experienced TTTS (Bahtiyar et al., 2007). However, these summations do not specify co-twin status (donor or recipient), although pulmonary stenosis presumably represents the recipient population. The original studies also do not separate donor or recipient twin status, so it is difficult to assess the potential relationship of atrial septal defects to fetal volume status or circulating mediators and angiogenic factors. Presumably, high-output failure in the donor twin or right ventricular outflow tract obstruction in the recipient both could result in increased shunting through the foramen ovale and acquired incompetence of the interatrial septum (passive enlargement such that the septum primum does not adequately cover the foramen ovale). It is unclear whether the clinically diagnosed “atrial septal defects” represent a true primary deficiency of tissue (due to ischemic necrosis, increased apoptosis, mesenchymal failure) or excessive secondary dilatation of the foramen due to shunt overload as the right ventricle fails. Recently, transposition of the great arteries has been identified in a recipient twin, but the donor additionally had a vein of Galen malformation. Although the coexistence of the lesions might reflect a common causal mechanism, their etiopathogenesis(es) is unclear (Steggerda et al., 2006).
CHD in donor twins appears to be very rare, but left-sided obstructive lesions might be expected due to complications of hypovolemia. However, of the 830 monochorionic diamniotic gestations reviewed by Bahtiyar et al. (2007), the only instances of coarctation of the aorta or hypoplastic left ventricle (left-sided obstructive lesions) were isolated to two cases that did not have TTTS. Thus, although the prevalence theoretically would be expected to be higher in donor twins in TTTS and small twin size correlates with the presence of structural defects in monochorionic diamniotic twins (Bahtiyar et al., 2007), the pathogenesis of these rarely encountered lesions appears to represent more than unusual sequelae of diminished blood flow.
The differential diagnosis for TTTS includes discordant severe IUGR, discordant structural fetal anomalies, congenital infection, chromosomal abnormalities, and ruptured membranes. The antenatal diagnosis is based on ultrasound findings. Nevertheless, there have been attempts to devise more definitive diagnostic techniques. Fisk et al. (1990) described fetal blood sampling in six cases compromised by TTTS. Difference in hemoglobin concentration of 5g per deciliter was found in only one pregnancy. Confirmation of a shared circulation was achieved in two pregnancies by transfusing adult Rh - negative red cells into the smaller fetus and then detecting them by Kleihauer–Betke testing in blood aspirated from the larger fetus. Bruner and Rosemond (1993) further reported successful fetal blood sampling in six of nine cases with the ultrasonographic diagnosis of TTTS. Hemoglobin difference was present in only one case. Shared circulation was demonstrated and confirmed in four (44%) of those initially identified by ultrasonographic criteria through the transfusion of O - negative red cells into the small twin and the performance of Kleihauer–Betke analysis on blood obtained from the larger twin. The author concluded that the currently accepted prenatal criteria are insufficient for the diagnosis of TTTS and suggested that the sonographic findings of marked growth discordance with oligohydramnios, polyhydramnios, monochorionic placenta, and like gender should more accurately be described as the twin oligohydramnios/polyhydramnios sequence.
The injection of intravascular pancuronium bromide has been suggested as an alternative to the injection of adult red cells to confirm TTTS (Tanaka et al., 1992). Paralysis of both fetuses can be detected through the examination of fetal heart rate tracings. There is an absence ofaccelerations noted with a reduction in fetal heart rate variability and a persistent tachycardia seen following pancuronium injection.
TTTS is generally diagnosed during the neonatal period by demonstration of a hemoglobin difference of greater than 5 g per deciliter (Rausen et al., 1965; Tan et al., 1979) and a difference in birth weight between twins of greater than 20% (Tan et al., 1979). Untimely umbilical cord clamping of either donor or recipient, erythropoietic changes, and reversed intrapartum shunting may result in false-positive and false-negative diagnosis when the determination is based on hemoglobin disparity alone. The cutoff value between normal and abnormal intertwin birth weight differences also remains controversial (Blickstein, 1990). In fact, all the classically accepted neonatal criteria of discordant hemoglobin, hematocrit, and weight have been challenged.
Danskin and Neilson (1989) found that hemoglobin differences of greater than 5 g per deciliter occur at similar rates in twins with dichorionic and monochorionic placentation. They reported birth weight differences greater than 20% equally in monochorionic and dichorionic pregnancies. Wenstrom et al. (1992) reviewed 97 cases of pathologically proven monochorionic twin pregnancies and observed all combinations ofweight and hemoglobin/hematocrit discordance. Of 97 twin pairs, 34 were discordant for weight, and in half of these the hemoglobin and hematocrit were concordant. In 18% of cases the smaller twin had the higher hematocrit, and in 32% the smaller twin had the lower hematocrit. The authors concluded that weight and hemoglobin/hematocrit discordance is common in monochorionic twins and in itself is not sufficient for a diagnosis of TTTS. Conflicting information regarding both the fetal and neonatal hematologic criteria for the diagnosis of TTTS, together with the potential risk inherent in fetal blood sampling, has led us to avoid this procedure at our institution for the definitive diagnosis of TTTS.
ANTENATAL NATURAL HISTORY
TTTS occurs in acute and chronic forms. In early pregnancy an acute transfusion may result in an early fetal death, resulting in the so-called vanishing twin syndrome. Later in pregnancy, TTTS may cause death of one or both twins (Figure 119-2). Sometimes, a rapid transfer of blood from one twin to the other occurs during delivery. In such cases the twins are similar in weight and length, but one is polycythemic and hypervolemic and the other is anemic and hypovolemic.
Death of both twins in midgestation as a result of twin-to-twin transfusion syndrome. The smaller, growth-restricted donor twin is on the left and the larger recipient twin on the right. (Courtesy of Dr. Joseph Semple.)
In the chronic form of TTTS, the transfusion ofblood from one twin to the other occurs over an extended period during the pregnancy. In chronic TTTS, the donor twin is generally hypovolemic and shows varying degrees of growth restriction. TTTS and placental insufficiency occur together in up to 20% of cases. In severe cases, the donor may die in utero and present at delivery as a fetus papyraceous. The recipient twin is hypervolemic, often larger than the donor, and may develop cardiac hypertrophy and congestive heart failure. Because of increased urine output, severe polyhydramnios frequently develops in the recipient twin that may predispose to premature delivery. Oligohydramnios is generally associated with the donor twin. The organ changes seen in donor twins in chronic TTTS resemble abnormalities observed in malnourished singletons. Weights of the heart, liver, spleen, thymus, and fetal adrenal cortex are proportionately smaller in the donor than in the recipient twin and suggest antenatal malnutrition (Naeye, 1965) (Figure 119-3). A much higher concentration of atriopeptin (atrionatriuretic peptide) has been reported in the serum from the recipient twin as compared with the donor twin in two cases ofsevere transfusion syndrome. More recently, Habli et al. have found that brain atrial natriuretic peptide (BNP) is significantly elevated in 130 cases of TTTS (Habli and Crombleholme, 2009). The elevated BNP levels were found to correlate with Cincinnati stage of TTTS cardiomyopathy (Habli and Crombleholme, 2009). One may infer from this that atriopeptin plays a role in the pathophysiology of the syndrome (Nageotte et al., 1989). Atriopeptin, produced by mammalian atria and BNP produced by the ventricles, are peptides that promote diuresis and vascular changes. In TTTS, atriopeptin and BPN released from the heart of the recipient may lead to increased urine output that results in polyhydramnios and vascular changes that in turn lead to hydrops (Nageotte et al., 1989, Habli and Crombleholme, 2009). Untreated, the natural history of TTTS is associated with a 60% to 100% mortality rate for both twins in severe or chronic cases (Benirschke and Kim, 1973; Cheschier and Seeds, 1988).
At the right is the paler, smaller heart of the donor fetus. At the left is the plethoric, larger heart of the recipient fetus.
In the assessment ofdiscordant growth in twins in utero it is important to differentiate TTTS from isolated growth failure of one twin. The cause of stuck twin syndrome includes twin-to-twin transfusion, fetal anomalies, placental insufficiency, and possibly abnormal cord insertion. A detailed anatomic survey is recommended to rule out any associated congenital abnormalities. Such a survey may be difficult if the fetus is stuck because of substantial oligohydramnios, which impairs ultrasonic visualization. Color Doppler studies are useful to visualize where the cord inserts into the placenta. In cases of TTTS, echocardiographic assessment of both donor and recipient twins is recommended and the Cincinnati staging system can be used to stratify TTTS cardiomyopathy into mild moderate and severe. In addition, we routinely perform ultra-fast fetal MRI to evaluate the fetal brains for signs of ischemia, hemorrhage or dilated venous sinuses that may be present in up to 8% of cases of TTTS at presentation (Kline-Fath et al., 2007). It is our practice to perform amniocentesis to exclude a chromosomal abnormality. Amniotic fluid is also sent for cytomegalovirus culture because of the reported association of stuck twin syndrome with viral infections. The definitive antenatal diagnosis is one of exclusion, and therapy is usually based on a presumptive diagnosis. It is our practice to inform patients of the various available treatment options, summarized in Table 119-2.
Delivery should be performed at a tertiary care center because most cases deliver less than 32 weeks’ gestation. Vaginal delivery may be attempted in cases in which TTTS has been diagnosed. It is critical to monitor the heart rates of both fetuses. A sinusoidal pattern on the fetal heart rate tracing may be a sign of fetal anemia. Of eight cases of TTTS monitored through labor by Goldberg et al. (1986), two pairs experienced severe fetal distress requiring emergency cesarean section. In another case, the recipient died of presumed intrapartum TTTS (Goldberg et al., 1986). The incidence of cesarean delivery in TTTS was reported to be 44% in Reisner et al.’s series (1993), but this has not been reported in other recent series.
Table 119-2Options Available for the Treatment of TTTS ||Download (.pdf) Table 119-2 Options Available for the Treatment of TTTS
|Observation only |
|Medical therapy |
|Serial amniocentesis with echocardiographic surveillance |
|Amniotic septostomy |
|Selective reduction by radiofrequency ablation or cord coagulation |
|Fetoscopic laser treatment |
Cord hematocrits should be measured at the time of delivery. Initial examination of the placenta should be performed by the obstetrician after delivery. Classically, the placenta of the donor twin looks pale and atrophied in comparison to that of the recipient twin that is red and hy-pertrophied. Because postnatal demonstration of transplacental vascular connections is an important criterion for the definitive diagnosis of TTTS, the placenta should be sent to the pathology department for further studies. Because many cases involve deep vascular shunts rather than superficial connections, vascular injection is necessary to exclude such connections (Blickstein, 1990).
Due to the poor perinatal outcomes associated with the disorder, expectant management of TTTS is not recommended except in incipient cases that do not meet criteria for TTTS (Fox et al., 2005). Treatment depends on the gestational age at diagnosis. Patients with early onset TTTS may opt for selective termination of one twin (usually the donor) or termination of the entire pregnancy. If TTTS develops later in pregnancy, treatment may be less aggressive depending on the disease severity and gestational age.
In the midtrimester, aggressive management is recommended. Medical management with digoxin has been attempted but has not shown to be effective (De Lia et al., 1985). Indomethacin is contraindicated due to reports of fetal demise (Jones et al., 1993). Current treatment options for severe TTTS include: (1) serial reduction amniocentesis, (2) amniotic septostomy, and (3) laser ablation of the anastomoses.
In serial reduction amniocentesis, an 18-gauge spinal needle is placed into the polyhydramniotic sac under ultrasound guidance (Malone and D’Alton, 2000; Johnsen, 2004). Provided the patient can tolerate the procedure, amniotic fluid is withdrawn until the fluid level returns to normal (DVP < 5 cm). Amnioreduction is repeated as often as necessary to maintain a near normal amniotic fluid volume. The mechanism by which this procedure restores the amniotic fluid balance has not been elucidated. Removing excess fluid from the sac with polyhydramnios may result in decreased pressure on the other sac or the placenta. This, in turn, may result in increased placental perfusion to the stuck twin with secondary improvement in its amniotic fluid. Studies have cited perinatal survival rates of 37% to 83% following this procedure (Malone and D’Alton 2000). The wide range in perinatal survival may be due to reporting bias, small sample sizes, and variation in the timing and amount of fluid removed. Large registries of TTTS pregnancies however, have reported survivals of 60% to 65% (Dickenson and Evans, 2000; Mari et al., 2001).
Amniotic septostomy is another option (Malone and D’Alton, 2000; Johnson et al., 2001). In this procedure, a 20-gauge spinal needle is inserted through the dividing membrane under ultrasound guidance. The amniotic fluid, then, sometimes equilibrates across the disrupted membrane. Similar to serial AR, the mechanism of action of this technique is unknown. It is possible that the defect in the membranes allows the donor to swallow a sufficient volume of fluid to augment its circulating blood volume, secondarily increasing its urine output. Studies regarding the effectiveness of this treatment modality have been conflicting. In one report of 12 cases, pregnancy was prolonged by 8 weeks with an 83% survival rate (Saade et al., 1998). In another report of 14 patients (7 managed by serial AR and 7 with amniotic septostomy) no differences in overall survival were noted. The septostomy patients, however, delivered significantly later. In another report, all three of the treated pregnancies were lost within 5 days secondary to preterm premature rupture of membranes (Pistorius and Howarth, 1999). In a more recent study by Saade et al., 32 patients were randomized to septostomy and 31 to AR. Similar outcomes were noted between the groups. Both groups had 65% survival (Saade et al., 2002). Because septostomy can result in an iatrogenic monoamniotic pregnancy that has its own inherent complications and risks, the procedure has been criticized. Likewise, comparing AR to septostomy is challenging because both procedures utilize AR, and, serial AR can be complicated by inadvertent septostomy.
Laser ablation of placental anastomoses is another invasive treatment option that has been utilized to correct the underlying pathophysiology of TTTS. Reported perinatal survival rates have ranged from 53% to 69% (Malone and D’Alton, 2000). De Lia et al. (1990) developed the technique for intrauterine ablation of vascular communications in the placenta with a fetoscopically directed neodymium-YAG laser. Three women who were carrying twins and who were at risk of pregnancy loss from acute hydramnios underwent the procedure at 18,22, and 22.5 weeks of gestation. Four of the six infants survived. De Lia et al. subsequently reported 26 patients with a mean gestational age of 20.8 weeks at the time of treatment. One patient has surviving triplets, eight have surviving twins, nine have a single survivor (two neonatal and seven fetal deaths occurred in this group and eight have no survivors). The cases with survivors were delivered for obstetric indications at a mean of 32.2 weeks. Fifty-three percent of the fetuses survived with 96% (27 of 28) developing “normally” at a mean age of 35.8 months. An identical survival rate of 53% was reported in a second series involving 45 cases of TTTS (Ville et al., 1995). The median interval between the endoscopic laser procedure and the delivery was 14 weeks. De Lia et al.’s surgical technique consisted of laparotomy (7- to 10-cm skin incision) under general anesthesia and insertion of a 3.85 × 2.9-mm fetoscope sleeve into the uterus. The technique has not gained widespread acceptance because of its invasive nature. Ville et al. (1995) described the percutaneous insertion of a 2-mm fetoscope into the amniotic cavity using continuous ultrasound visualization under local anesthesia.
The goal of coagulation of all superficial placental vessels is to interrupt the vascular communication between the circulation of the two fetuses (Figure 119-4). This direct treatment of the underlying pathophysiology of TTTS has been cited as a major advantage over other techniques (De Lia et al., 1995; Ville et al., 1995).
Vascular anastomoses in monochorionic twins. (Courtesy of Dr. Joseph Semple.)
In a series of 132 pregnancies with TTTS managed by fetoscopic laser ablation of placental vessels, 55% of infants survived, and there was at least one survivor in 73% of the cases (Ville et al., 1998). The rate of neurologic handicap after 12 months of follow-up was 4%, which was lower than the authors’ previous experience with serial reduction am-niocentesis. The authors concluded that serial reduction am-niocentesis appears to provide similar overall survival results, but there was less neurologic morbidity in the laser group.
In a study of TTTS from Germany, 73 patients at a single center were prospectively treated with fetoscopic laser ablation, while 43 patients at a separate center were prospectively treated with serial reduction amniocentesis (Hecher et al., 1999). Patients in the fetoscopic laser group had a higher proportion of pregnancies with at least one survivor, fewer fetal deaths, higher gestational age at delivery, and fewer cases of abnormal sonographic findings in the brain of survivors. It was therefore concluded that fetoscopic laser ablation is a more effective treatment for TTTS than serial reduction amniocentesis.
Senat et al. (2004) recently published the results of the European prospective multicenter randomized controlled study of endoscopic laser (semiselective technique) versus serial AR for the treatment ofsevere TTTS. All patients were between 15 and 26 weeks’ gestation. Interim analysis demonstrated a significant benefit to the laser group. As result, the study was stopped after 142 patients had been randomized. Compared to the AR group, the laser group had a higher likelihood of survival of at least one twin to 28 days of life (76% vs. 56%) and 6 months of age (76% vs. 51%). The median gestational age at delivery was significantly greater in the laser group than in the AR group (33.3 weeks vs. 29.0 weeks). Thirty patients in the laser group (42%) and 48 in the AR group (69%) delivered before 32 weeks. Neonates from the laser group also had a lower incidence of periventricular leukomalacia and were more likely to be free of neurologic imaging abnormalities at 6 months of age (52% vs. 31%).
The overall survival in the laser arm was 57%, which was consistent with survival rates in previous reports of nonselective fetoscopic laser treatment (53%) (De Lia et al., 1995; Ville et al., 1995). This rate is significantly lower, however, than the survival reported with selective fetoscopic laser photocoagulation (SFLP) (64–68%) (Hecher et al., 1999; Dickinson and Evans, 2000). Of particular concern is the poor survival observed in the AR arm of 39%, which is significantly lower than previously reported (60–65%) (Elliott et al., 1991; Pinette et al., 1993; Dickinson and Evans, 2000; Mari et al., 2001). Antenatal, peripartum, and neonatal care was provided by the referring hospital, and lack of standardization mayexplain some of these differences (Fisk and Galea, 2004). The decreased survival in the AR group may reflect the higher pregnancy termination rate in the AR group (16 vs. 0 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 (Dickinson and Evans, 2000). Reliable assessment of neurologic outcome is critical when assessing efficacy of treatment for TTTS. Although the rate of abnormality on neurologic imaging was lower in the laser group (7% vs. 17%), long-term neurodevelopmental assessment has revealed no difference in outcome between survivors treated by fetoscopic laser and those treated by AR (Ortqvist et al., 2006).
The National Institutes of Health (NIH)-sponsored TTTS trial is the only other prospective randomized trial comparing survival among those receiving AR versus SFLP (Crombleholme et al., 2007). This trial differed from the Eurofoetus trial in several important aspects. First, to qualify for the NIH Trial, the TTTS had to fail to respond to a qualifying amniocentesis. The rationale for this requirement was to eliminate those who were more likely to respond to AR, the so-called “single amnio paradox.” Second, patients were candidates only if the TTTS presented earlier than 22 weeks of gestation, and no Stage I patients were candidates for the trial. These two requirements were substantially different from the Eurofoetus trial in which women were randomized into the trial up to 26 weeks of gestation, and 52% of those entered were Stage I (Senat et al., 2004).
The NIH study was stopped early, after 42 women were randomized, when the Trial Oversight Committee detected a trend in adverse outcome affecting the recipient twin in one treatment arm and recommended to the Data Safety Monitoring Board that the trial be stopped to allow biostatistical analysis of the adverse trend. Results of the NIH TTTS trial showed no statistically significant difference in overall neonatal survival to 30 postnatal days (60% vs. 43% p = NS) or neonatal survival of one or both twins in the same pregnancy (75% vs. 65%, p = NS) in cases of severe TTTS treated by either AR or SFLP. Despite these overall results, a statistically significant worse fetal survival was observed among recipient twins in pregnancies treated by SFLP compared with those treated by AR. This apparent conundrum can be accounted for by recipient fetal losses in the SFLP arm being balanced by increased treatment failures among recipients in the AR arm. These results suggest that, in these highly selected cases of severe TTTS, neither treatment is superior to the other. Once TTTS reaches this degree of severity, the mortality among recipients is considerable, but the losses may occur at different times, depending on treatment. The impact of TTTS severity on fetal survival is supported further by the significantly worse fetal survival among recipient twins in Stages III and IV compared with those in Stage II. One of the strongest predictors of recipient demise is echocardiographic evidence of TTTS cardiomyopathy. The losses of fetal recipients treated by SFLP usually occur within 24 hours of the procedure. In contrast, the recipients treated by AR are not lost following the procedure, but there is progressive TTTS cardiomyopathy, as reflected by more recipients in the AR arm meeting criteria to be declared treatment failures. Taken together, these data suggest a disproportionate impact of TTTS cardiomyopathy on recipient survival in advanced stages of TTTS no matter what treatment they receive.
Recently, Rossi and D’Addario (2008) reported a Cochrane review of TTTS with a meta-analysis that included data from both the Eurofoetus and NIH trials. The conclusion drawn from this analysis was that SFLP of TTTS is preferred over AR when it is available and AR is preferred when SFLP is not available. The results of this analysis likely are skewed toward fetoscopic laser based on the small numbers of individuals included from the NIH trial (n = 42) compared with the number included from the Eurofoetus trial (n = 142).
AR is readily available, less costly, and less invasive; laser therapy is only available at select institutions and requires specialized training. Although it makes sense to use AR where treatment options give similar results, it would be prudent to move promptly to laser therapy if rigorous studies can prove that this therapy has better short- and long-term outcomes in the setting of advanced disease.
For patients who respond to AR, the overall survival rate has been 88% (Crombleholme et al., 2006). In those cases in which echocardiographic progression is detected despite AR, the overall survival rate when SFLP is performed is 80%. The difference in survival between responders to AR and those who progress to SFLP is not statistically significantly different, suggesting that survival was not compromised by an initial trial of AR before progressing to SFLP.
Both acute and chronic cases of TTTS must be managed expeditiously by trained neonatologists. Because the incidence of prematurity is so high, many complications of prematurity are present, including the need for respiratory support, transfusion, and supplemental glucose. Specific problems unique to newborn cases of TTTS include severe anemia in the donor and severe polycythemia and hypervolemia in the recipient newborn. Either one or both twins may have hydrops. Exchange transfusions may be necessary to correct the anemia and polycythemia. If TTTS cardiomyopathy is present, ionotrophic support may be indicated for the recipient twin. Echocardiographic assessment should be performed in any recipient with TTTS cardiomyopathy.
No surgical treatment has been described for newborns with TTTS.
One of the concerns associated with in utero treatment for TTTS is that prolongation of pregnancy might produce survivors with excessive neonatal or infant complications (Mahony et al., 1990). If one fetus dies in utero, the surviving twin is at risk for multiorgan damage including severe neurologic compromise. Even if both twins survive, the pathophysiology of TTTS can result in adverse neurological sequelae to one or both (Cincotta et al., 2000; Dickinson and Evans, 2000; Mari et al., 2001; Sutcliffe et al., 2001; Banek et al., 2003; Lopriore et al., 2003; Dickinson et al., 2005).
In older literature, thrombocytopenia has been suggested as a cause of cataracts, impaired hearing, and growth restriction of the donor twin (Corney and Aherne, 1965). Intrauterine growth deficiency of the brain (Naeye, 1963) and profound neonatal hypoglycemia (Reisner et al., 1965) have been implicated as a cause for cerebral impairment of the donor, resulting in subsequent lower intelligence as compared with the recipient twin. Cardiomyopathy and associated cardiac dysfunction has been reported (Mahony et al., 1990; Elliott, 1992). In one study, five of five recipient twins were found to have cardiomegaly and tricuspid regurgitation prenatally; four had cardiac dysfunction after birth (Zosmer et al., 1994). In Elliott’s (1992) experience there were two cardiac abnormalities in 12 fetuses (one critical aortic stenosis, one cardiopathy). Renal cortical necrosis (Dimmick et al., 1971; Feingold et al., 1986) and brain infarction have been reported in the donor twin (Mahony et al., 1990). These complications have also been described in the surviving co-twin of intrauterine fetal death in utero. The mechanism may be hypovolemia and ischemic injury in the smaller donor twin (Elliott, 1992).
Although much attention has focused on the effect of treatment on survival in TTTS, the neurologic morbidity among survivors frequently is underappreciated. The International Amnioreduction Registry tracked 223 women who had TTTS diagnosed before 28 weeks’ gestation and were treated with serial aggressive AR (Mari et al., 2001). Of those infants who survived to 4 weeks of age and underwent clinically indicated cranial ultrasonography, 24% of recipient (26/109 scanned) and 25% of donor twins (22/88 scanned) had abnormal findings. Findings included severe intraven-tricular hemorrhage, ventricular dilation, cerebral echogenic foci, cerebral cysts, and periventricular leukomalacia among other less common lesions. Eighty infants died before reaching 4 weeks of age, and how many of these would have had abnormal imaging if cranial ultrasonography had been performed is unknown. Among patients in the TTTS Registry from Australia and New Zealand, most of whom had been treated with AR, the rate of abnormal cranial ultrasonog-raphy findings was similar at 27.3% (Dickinson and Evans, 2000). The rate of periventricular leukomalacia in this group was 10.8%, which is particularly important due to the association of this lesion with cerebral palsy. In another small series of patients treated with AR, the rate of abnormal neonatal cranial ultrasonography findings was as high as 58% (Denbow et al., 1998). It is important to recognize, however, that neuroimaging does not always correlate with neurodevelopmental outcome. An infant who has normal findings on head ultrasonography and MRI can be neurodevelopmentally devastated, and an infant who has evidence of leukoencephalomalacia on imaging studies can be neurodevelopmentally intact.
Only a few studies have reported longer-term neurodevelopmental outcome. When interpreting these studies, it is important to appreciate the neurodevelopmental outcome in monochorionic twins who do not have TTTS. The incidence of severe neurodevelopmental abnormalities in monochorionic twins without TTTS is 6% (Lopriore et al., 2003). TTTS survivors who develop neurologic handicap and mental retardation do not always have abnormal neonatal ultrasonog-raphy results. Similarly, not all children who have abnormal ultrasonography findings have clinically significant neurodevelopmental deficits. In one small study that followed TTTS survivors for a mean of 6.2 years (range, 4–11 years), the incidence of cerebral palsy was 26% (5/19 infants) in the group treated by serial AR. All of these children had abnormal mental development in addition to motor deficits. Of note, three of the five children had normal findings on neonatal head ultrasonography. In the combined cohort of children whose mothers had been treated with AR or conservative treatment, 22% (5/23) who did not have 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 who receive AR and other treatment modalities, however, it is unlikely that such a cohort ever will be available for comparison.
Studying infants from pregnancies complicated by TTTS and treated with AR, Mari et al. (2001) detected a rate of cerebral palsy of 4.7% (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. (2003) may be related to the latter study group having more severe disease, with all the patients diagnosed before 28 weeks’ gestation versus up to 33 weeks’ gestation in the study by Mari et al. Of note, in the Mari study, nine survivors had mild speech or motor delay.
Wee et al. (2005) studied the long-term neurologic outcome of 52 children from 31 TTTS pregnancies who survived to more than 18 months, most of whose mothers had been treated with AR. The comparison was a regional cohort of term and preterm infants, with most born very preterm. In addition, the TTTS babies were compared with matched singleton and twin control groups. The mean intelligence quotient (IQ) of TTTS survivors was significantly lower than the comparison cohort, due primarily to a 13-point IQ reduction in those children born before 33 weeks’ gestation. There was no difference in the rate of cerebral palsy (5.8% for TTTS vs. 4.9% for very preterm twins vs. 3.3% for very preterm singletons) or behavioral test results 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 generally are more likely to experience neurologic compromise.
Even fewer studies have examined the long-term outcome of survivors of TTTS treated with intrauterine laser photocoagulation therapy. Banek et al. (2003) reported that in 89 such children, 78% showed normal development at a median age of 22 months. Eleven percent had minor neurologic abnormalities, including strabismus, mildly delayed motor development, or mildly abnormal speech. The remaining 11% suffered significant neurologic deficiencies, including cerebral palsy, hemiparesis, and spastic quadriplegia. Of note, significantly more children in the neurologically impaired groups were born very preterm. Also of importance, two infants from the most severely affected group had abnormal brain scan results before laser treatment. The findings of this study are consistent with those of Sutcliffe et al. (2001) who reported a cerebral palsy rate of 9% in children after in utero treatment with laser therapy for TTTS. Graef et al., (2006) in a report of 167 TTTS survivors who had been treated by fetoscopic laser, found normal neurodevelopmental testing results in 86.8% of cases, with 7.2% of infants having minor neurologic deficiencies and 6% having major neurologic deficiencies such as cerebral palsy, hemiparesis, and quadriplegia. These findings were not unlike those in follow-up of monochorionic twins without TTTS (Adegbite et al., 2004), and the most severely affected children were delivered prior to 28 weeks’ gestation, suggesting an important influence of gestational age on neurodevelopmental outcome. Similarly, Ortqvist et al. (2006) reported the neurodevelopmental outcome of 114 survivors treated in the Eurofoetus trial in which 13.2% had evidence of a major neurodevelopmental abnormality. However, there was no difference between those who had been treated by laser and those treated by AR. Perinatal factors, including gestational age at delivery and Apgar score, correlated with adverse outcome.
Of note, earlier and more sensitive antenatal detection of central nervous system injury (Crombleholme, 2003; Quarello et al., 2007) has been reported recently with the adjunct use of MRI techniques. MRI has enabled the detection of cerebral venous sinus dilatation and more clearly delineated central nervous system lesions. The improvements in antenatal detection may result in further improvements in clinical management (Crombleholme, 2003) and reduced morbidity and its severity in survivors.
GENETICS AND RECURRENCE RISK
There are no reports ofrecurrence of TTTS in the literature.
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