C620R9018.rtf
Do We Know How To Effectively Treat Twin-Twin Transfusion Syndrome?
T.M. Crombleholme
The Center for Fetal Diagnosis and Treatment at The Children's Hospital of Philadelphia and the University of Pennsylvania School of Medicine, Philadelphia, PA, U.S.A.
The natural history of severe TTTS is well established with mortality approaching 100% if left untreated, especially when it presents at less than 20 weeks' gestation (1-3). As a result, numerous treatments have been proposed including selective fetocide, cord coagulation, sectio parva, placental blood letting, maternal digitalis, indocin, serial amnioreduction, microseptostomy of the intertwin membrane, and nonselective or selective fetoscopic laser photocoagulation. However, in the United States serial amnioreduction has been the standard therapy of TTTS.
Amnioreduction was first employed as a means to control polyhydramnios in the hope of prolonging the pregnancy (4). In uncontrolled series, serial amnioreduction appeared to improve survival. Moise, in a review of 26 reports dating from the 1930s of 252 fetuses, found an overall survival of 49% (5). However, the survival in more recent series with more consistently aggressive serial amnioreduction to reduce amniotic fluid volume to normal have ranged widely from as low as 37% to as high as 83% (1,6,7). However, these retrospective series are comprised of small numbers of patients from a range of gestational ages as well as a broad spectrum of severity of TTTS. The severity of TTTS clearly varies with the gestation age at which it presents, and this may have a profound impact on the observed mortality with any treatment strategy employed. The earlier in gestation TTTS presents the worse the prognosis and, conversely, the later in gestation TTTS presents the better the prognosis as data from the Amnioreduction Registry shows (7). Experience with patients presenting with advanced TTTS prior to 22 weeks gestation and absent end diastolic flow in the recipient umbilical artery, survival with aggressive serial amnioreduction was only 13% and with absent end diastolic flow in the donor umbilical artery was 33% (8).
The paradoxical resolution of oligohydramnios after a single amnioreduction was first suggested by Saade to be due to puncture of the intertwin membrane(8). This intertwin septostomy was proposed as a treatment for TTTS to restore amniotic fluid dynamics without the need for repeated amnioreduction. In a small multicenter series of 12 patients, Moise et al., reported an 81% survival with microseptostomy(9). One objection to this approach is the possibility it would result in a large septostomy creating an essentially monoamniotic sac with the attendent risk of cord entanglement (10). For this reason, a "microseptostomy" has been proposed to prevent this complication. However, not only was the series small and uncontrolled, there was no report of neurologic or cardiac morbidity. In a direct comparison, albiet a small retrospecitve single institution series, of serial amnioreduction vs microseptostomy Johnson et al observed no survival advantage with either therapy (11). But microseptostomy did appear to prolong pregnancy compared to amnioreduction. In our experience with microseptostomy performed in severe TTTS presenting prior to 20 weeks gestation this treatment was able to restore amniotic fluid dynamics in almost every case. However, in two thirds of the cases there was hemodynamic evidence of progression of TTTS necessitating either fetoscopic cord coagulation or selective fetoscopic laser photocoagulation to salvage the twins.
The first treatment for TTTS that attempted to treat the underlying chorioangiopagus was reported by DeLia et al (12,13). Fetoscopic laser was used to photocoagulate vessels crossing the intertwin membrane. In the first series of cases of TTTS, DeLia reported a survival of 53% in 26 patients (12). While survival was not significantly better than previous reports with serial amnioreduction, the neurologic outcome was: 96% of survivors had normal neurologic outcome. Other groups from Europe have reported similar survival with fetoscopic laser photocoagulation. Ville et al, reported 53% survival with a non-selective laser technique which was better than the survival observed with historical controls at the same center with serial amnioreduction (37%) (13). There also appeared to be an improved neurologic outcome in fetuses treated by laser. Non-selective fetoscopic laser photocoagulation of all vessels crossing the intertwin membrane may be problematic as the intertwin membrane often bares no relation to the vascular equator of the placenta. This may result in sacrifice of vessels not responsible for the TTTS, resulting in a higher death rate of the donor twin from acute placental insufficiency. More recently a selective laser photocoagulation technique has been reported with survival of 73% (14). The selective technique does not photocoagulate every vessel crossing the intertwin membrane, but only direct, arterial-arterial and veno-venous, connections are photocoagulated along with any unpaired artery going to a cotyledon with the corresponding vein (and vice versa) going to the opposite umbilical cord. In a non-randomized comparison of patients treated by serial amnioreduction at one center and selective laser photocoagulation at another the overall survival was not statistically significantly different (61% for laser vs 51% for serial amnioreduction) (15). However the survival of at least one twin with laser photocoagulation was 79% while survival of at least one twin with serial amnioreduction was only 60% (15). Unfortunately, this was not a controlled trial and patients were not randomized.
While much attention has focused on the effect of treatment on survival in TTTS the morbidity among survivors has been under appreciated. Among the most important is the severe neurologic morbidity that is observed in 18-26% of survivors (12-15). Due to the shared placental circulation, with death of one co-twin an acute fall in blood pressure may cause the placental resistance to fall resulting in decrease in the cerebral perfusion pressure and ischemic injury to the brain of the other twin. Brain injury can occur in TTTS even in the absence of co-twin demise, however (7). The incidence of neurologic injury with serial amnioreduction varies from 18% to 26%. In contrast, fetoscopic laser photocoagulation has demonstrated lower incidence of neurologic morbidity (defined as sonographic abnormality) of 4-6% (12-15). However, none of these abnormal ultrasound findings have been correlated with long-term neurodevelopmental outcome. In addition, because ultrasounds may not be obtained in the immediate postnatal period, it is not possible to determine if the neurologic morbidity is due to events in utero or due to perinatal or postnatal events in this high risk group of premature infants. Long-term neurologic outcome in TTTS has never been evaluated.
All of the treatments discussed above have anecdotal evidence suggesting that they improve survival in TTTS. It is not clear which therapy is best under what circumstances. In most centers the current standard of care in the United States is serial amnioreduction. Microseptostomy is practiced by few and a prospective study has yet to be completed evaluating its efficacy. Fetoscopic laser photocoagulation is available in only a few centers and the lack of controlled trials has limited enthusiasm for this more invasive therapy.
At present it is not known which therapy for TTTS is best for specific patients, for either survival or neurodevelopmental outcome. Crombleholme et al, have begun an NIH sponsored multicenter prospective randomized controlled trial comparing aggressive serial amnioreduction with selective fetoscopic laser photocoagulation for severe twin-twin transfusion syndrome presenting prior to 22 weeks gestation. It is hoped that this controlled trial will address many of the questions that remain unanswered about the treatment of severe TTTS (16).
References
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16. Crombleholme TM, et al: Twin-Twin Transfusion Syndrome Trial 1RO1-HD41149-01