Twin‐twin transfusion syndrome: the good news is; there is still room for improvement …

In the current issue, two fetal medicine centers report their experience with invasive fetal therapy for the twin-twin transfusion syndrome (TTTS). TTTS affects 1 in 10 monochorionic (MC) twin pregnancies between 16 and 26 weeks and is the most important cause of death and handicap in MC twins (1). During intrauterine life, MC twins not only share a single placenta but nearly all have anastomoses linking the two fetal circulations. This shared circulation may lead to imbalances such as TTTS, but also makes the wellbeing of one twin critically dependent on that of the other. Containment of the devastating impact of TTTS starts in the first trimester with a correct determination of chorionicity. Indeed, the diagnosis of a twin pregnancy no longer suffices and each scan report should specify whether it concerns a dichorionic or rather an MC pair (2). MC pregnancies, which constitute 30% of all spontaneously conceived twins and 4% of twins resulting from assisted conception (3), all deserve a fortnightly follow-up to timely detect TTTS. TTTS is an easy and straightforward diagnosis that does not require advanced scanning skills. The diagnosis is based on the presence of polyhydramnios (≥8 cm prior to 20 weeks and ≥10 cm after this) and a distended bladder in one twin together with oligohydramnios (≤2 cm) with an empty bladder in the other. Usually, the visualization of a free floating intertwin membrane and two equally sized bladders is enough to rule out TTTS. Because TTTS occurs in the pre-viable period, its prognosis is dismal without treatment. Polyhydramnios-related miscarriage or the preterm birth of two sick neonates is common, as well as intrauterine demise of one or both twins. Fetoscopic laser coagulation of all anastomoses is currently the best treatment, regardless of disease severity (4). Although survival doubles from approximately 30% in untreated cases (5) to 60% after laser therapy, outcome is still far from perfect. In experienced hands, about 50 to 60% of parents take home twins, 30% take home one baby and 10 to 20% have no surviving infant (6). Most double losses are miscarriages or severe preterm births and less commonly double intrauterine demises mostly related to missed anastomoses. On the other hand, most single deaths are an intrauterine demise, typically within the first postoperative weeks and probably related to unequal placental sharing, cardiac failure, perioperative exsanguination or missed anastomoses. Of surviving infants, 11% have some form of developmental impairment, of which cerebral palsy is the most common, being present in 5% (7). The single most important predictor of impairment is an early gestational age at birth (8). Therefore, at best only 40% of parents will ultimately take home two healthy babies. As with any surgical technique, experience matters. This is suggested by many reports, but is most clearly demonstrated in the series by Hecher and co-workers, which showed an improvement of 10% in overall survival and of nearly 20% in double survival between the first 70 and the 200th to 400th procedures (9,10). So, even after 200 cases, outcome continued to improve. For fetoscopic laser, the surgeon needs to be familiar with endoscopy and ultrasound guided fetal procedures. Also, in order to decide on the best site for trocar entry, one must to be able to predict where the vascular anastomoses are likely to be found. Obviously, familiarity with what an anastomosis looks like is essential to select only the anastomosing vessels that require coagulation. Finally, positioning of the patient, manipulation of the uterus and coagulation through the cannula to tackle the difficult anterior placenta, are skills that are only acquired by extensive experience. As such, increased operator experience may result in fewer missed anastomoses, less coagulation of noninvolved vessels and a shorter operation time, thereby improving survival. On the other hand, severe unequal placental sharing, a pre-moribund state of one of the twins or a dilated cervix at the time of diagnosis are unlikely to lead to a dual survival, no matter how experienced the operator is. Studies on the actual learning curve of laser suggest that in a setting with hands-on training by an experienced operator 20 procedures are sufficient to achieve acceptable results, whereas 60 procedures are required if training is obtained through observation only (11). Obviously, much more is required than just one good surgeon. Ideally, three experienced operators should be available to cover a 24 hour/7 day service. The center also needs to have access to state-of-the-art equipment (including back–up material in case of equipment failure) and be able to treat possible early as well as late complications, such as intra-amniotic bleeding, recurrence of TTTS or the rare cases with antenatal cerebral damage. The availability of a specialist midwife, social worker or psychologist is not redundant to support the parents through this very stressful and uncertain time. Finally, collection of outcome and placental injection studies are both useful to monitor the center's performance. In the current issue, two articles report on the outcome of TTTS treated in fetal medicine centers in Sweden and Denmark. Access to care is an important concept in medicine, but the importance of experience argues against the scattering of this experience over too many centers. Indeed, it is generally recommended that laser should be available at centers managing at least 20 cases a year (12). Nevertheless, one has to bear in mind three facts. First, not all TTTS cases will be eligible for laser treatment: parents may opt for a termination of pregnancy, cases may be missed, referred elsewhere or present too late with intrauterine demise or a dilated cervix, or there may be a severe congenital anomaly in one twin. This implies that in order to perform 20 laser procedures, one needs at least the referral of 40 TTTS cases and thus cover an area 100 000 deliveries a year. Second, 20 interventions a year is almost certainly too little to achieve competence and to maintain experience of three surgeons, so at least 60 procedures a year are required and thus a catchment area of 300 000 births. Finally, research to improve outcome is best done in centers of excellence with a high-volume load. Therefore, although some may object to the centralization of these procedures in a limited number of centers, it seems in the patient's best interest. The Swedish study by Ek and co-workers (13) report on their experience of 66 laser procedures over an eight year time period. The lead surgeon was an observer in a high-volume center and over the years, four other physicians have been participating in the program. According to the expected learning curve, 60 procedures would be necessary only to achieve an acceptable performance of the lead surgeon. At least one live-born twin was achieved in 75% of pregnancies. The authors state that these figures are comparable to previous reports, but in fact studies that only report their live-birth rates overestimate survival. As such, the reports used for comparison all describe the neonatal survival rates (up to at least 4 weeks after birth), which is the most relevant parameter and more accurately reflects true survival. In our series, the neonatal death rate is about 8%. In other words, our live-birth rate is 8% higher than our neonatal survival rate (8). Not only is there no information on neonatal mortality in that series, also information on neonatal morbidity, a strong predictor of long-term outcome, is lacking. Although the authors should be congratulated for reporting their outcome, it is hoped that an increased case load will result in a more detailed report in the near future. The second article from Denmark by Sundberg and co-workers (14) reports on the outcome of 55 TTTS cases treated with laser coagulation and 49 cases treated with selective feticide by umbilical cord coagulation. The key message of their report is that selective feticide is an acceptable treatment alternative to laser surgery. This statement is definitely open for debate. First, the maximum survival rate is only 40%, as one twin is necessarily lost. Second, in contrast to laser surgery, there are no reports with standardized neurodevelopmental follow-up after cord coagulation. Indeed, theoretically and in the assumption that the risk of impairment is independent, the risk of at least one twin having impairment is only half as high in single survivors (1 in 10) than in double survivors (1 in 5), but this is at the cost of the loss of one infant. Finally, as mentioned above, preterm birth is the main cause of impairment after laser. Preterm birth equally occurs after cord coagulation. As the authors observed in their series, cases treated with cord coagulation delivered as early as those treated with laser. In fact, in our own series of cord coagulation, 20% delivered prior to 32 weeks and such early preterm birth accounted for all cases with postnatal death and handicap (15). In our center, we will only discuss the option of cord coagulation as a back-up measure in stage III and IV TTTS, if for technical reasons it is anticipated it may not be possible to target all anastomoses. It is our experience that even in these selected cases; parents have difficulty to consent to a selective feticide and would want everything done to salvage both twins. Of course, parents have the choice to opt for a termination of pregnancy, but we would not consider this to be a treatment. In view of the 20% loss rate of the remaining twin, the 20% risk of early preterm birth and in the best estimates an 8% risk of impairment (15), it also seems difficult to defend selective feticide as an alternative to a termination of the entire pregnancy, as is proposed by the authors. Obviously, if one of the twins has a severe anomaly or in cases with recurrence where a re-laser is no longer possible, selective feticide is the obvious choice to safeguard the survival of at least one healthy baby. As a conclusion, TTTS affects 1 in 10 MC twin pregnancies and because of the bleak outcome without timely treatment, MC twin pregnancies should be identified in the first trimester and receive two-weekly follow-up. Laser coagulation of the anastomoses has dramatically improved the survival in TTTS, but the postoperative mortality and morbidity remain high and there is certainly room for improvement. Although survival is determined by many factors and operator experience is difficult to measure, as with any surgical procedure, these procedures are best concentrated in centers of excellence to ensure adequate competence, not only to perform the procedure itself, but also to manage the possible complications, to guarantee adequate follow-up and to allow research projects with sufficient numbers. In the absence of proof that selective feticide reduces the risk of handicap, laser coagulation of the vascular anastomoses should, at least in our opinion, remain the treatment of choice. Liesbeth Lewi, Roland Devlieger, Luc De Catte and Jan Deprest 1 Fetal Medicine Unit, Department of Obstetrics and Gynecology, University Hospitals, Leuven, Belgium, E-mail: [email protected]