Selective Fetoscopic Laser Photocoagulation of Superficial Placental Anastomoses for the Treatment of Severe Twin-Twin Transfusion Syndrome

OBJECTIVE: To report our initial institutional experience with fetoscopic laser photocoagulation of placental anastomoses in severe twin-twin transfusion syndrome using a 1.0 mm endoscope. METHODS: Between July 2006 and June 2008, 19 monochorionic diamniotic twin pregnancies complicated by severe TTTS (Quintero stages III and IV) underwent fetoscopic laser therapy. Perinatal data were prospectively collected and compared according to the Quintero stages. RESULTS: Nine patients were classified as stage III and ten as stage IV. The Mean gestational ages at diagnosis and procedure were 20 (range: 17–25) and 22.0 (range: 19.0–26.0) weeks, respectively, with no statistical difference between the two groups. Preterm premature rupture of the membranes occurred in two cases (10.5%), and spontaneous preterm delivery in eight (42.1%). Overall mean gestational age at delivery was 32.1 (range: 26.0–38.0) weeks. Prematurity was more severe in stage IV patients (p<0.01). Among all cases, the overall survival rate was 52.6%, and the percentages of pregnancies with survival of both babies and at least one twin were 26.3% and 78.9%, respectively. In the case of stage III patients, the overall survival rate was 61.1%. Of the stage III pregnancies, 33.3% resulted in both babies surviving, and 88.9% of these pregnancies resulted in at least one surviving twin. For stage IV, as the corresponding statistics were 45.0%, 20.0% and 70.0% respectively. CONCLUSIONS: Our initial institutional experience with 1.0 mm fetoscopic laser therapy for severe TTTS showed results similar to those reported in the literature for larger endoscopes.

The severity of the disease is usually assessed by the Quintero staging system: 27 Stage I is defined as oligohydramnios (deepest vertical pool ≤ 2cm) in the donor and polyhydramnios (deepest vertical pool ≥ 8cm) in the recipient; Stage II is denoted by donor anuria (anamnios and absence of fetal bladder -"stuck twin"); Stage III is characterized by critically abnormal Doppler ultrasonography in either the arterial system of the donor or the venous system of the recipient; Stage IV is present when there is fetal hydrops; and Stage V occurs with the mortality of one or both twins.
To the best of our knowledge, most centers use endoscopes of 2.0 to 3.0 mm to guide the fetoscopic laser ablation of superficial placental anastomoses, and there have been no previous reports of the use of a narrower endoscope for this procedure.
Therefore, the objective of the present study was to report our initial clinical experience with fetoscopic laser photocoagulation for severe TTTS using a 1.0 mm endoscope, focusing on perinatal outcomes and maternal complications consistent with the Quintero staging standard.

METHODS AND PATIENTS
From July 2006 to June 2008, a prospective study was conducted in a tertiary fetal medicine center. Fetoscopic laser photocoagulation was performed in 19 monochorionic diamniotic twin pregnancies complicated by severe TTTS. All patients were referred from obstetricians or other fetal medicine centers. All patients gave written consent after extensive counseling. This protocol was approved by the local ethical committees. Before laser treatment, detailed fetal morphological ultrasound examination and echocardiography were performed in order to assess fetal biometry, anomalies, deepest vertical pool, placental location and Doppler sonography of the umbilical arteries, middle cerebral arteries and ductus venosus.
Inclusion criteria for fetoscopic laser photocoagulation were: monochorionic diamniotic pregnancies complicated with severe TTTS (polyhydramnios in the recipient twin's amniotic cavity with the deepest vertical pool ≥ 8 cm and oligohydramnios in the donor twin with the deepest vertical pool ≤ 2 cm; Stages III and IV according to the Quintero classification 27 ) at a gestational age of less than 26 weeks. Exclusion criteria were fetal death, fetal malformation before procedure, rupture of membranes and preterm labor. During the study period, fetoscopic laser therapy was not offered for Stage I TTTS.
Fetoscopic laser therapy of the superficial placental anastomoses was performed under local maternal anesthesia (20 ml of 1% lidocaine injected into the skin and subcutaneous tissue) followed by percutaneous insertion into the amniotic cavity of a 2.2 mm specially designed trocar with two separate work channels for a 1 mm fetoscope (11510 A, Storz, Tuttlingen, Germany) and a 0.6 mm neodymium fiber, to allow the use of yttriumaluminum-garnet or diode laser equipment. In pregnancies with a completely anterior placenta, we used a 30° trocar of the same size and diameter. Superficial inter-twin placental anastomoses were directly identified ( Figure 1a) and coagulated (Figures 1b-d). At the end of the selective laser ablation procedure, amniotic fluid was drained through the sheath after removing the fetoscope until a vertical pool of 4-6 cm was confirmed under ultrasound. Prophylactic tocolytics and antibiotics were administered perioperatively. All the patients were hospitalized for 24 to 48 hours after the procedure and were followed by weekly ultrasound examinations.
The following prenatal and neonatal data were collected prospectively: gestational age at diagnosis, gestational age at fetoscopic laser photocoagulation, survival rates (either both fetuses or at least one twin), fetal mortality and neurological morbidity (intraventricular hemorrhage, periventricular leukomalacia, ventriculomegaly or cerebral palsy) during hospitalization for up to 30 days. All data were analyzed according to the Quintero stage. Categorical variables such as survival and stage were analyzed using the χ 2 test. Interval variables such as gestational age were analyzed using the Student's t test. Statistical significance was confirmed when p ≤ 0.05.

RESULTS
A total of 23 monochorionic diamniotic pregnancies met the initial inclusion criteria. However, three patients were excluded because preterm labor occurred before the laser procedure could be performed. One additional patient was excluded because she was bearing triplets. For the 19 pregnancies that were included in the present study, severe TTTS (stages III and IV) was confirmed using ultrasound examination. The mean gestational age at diagnosis was 20 (range: [17][18][19][20][21][22][23][24][25] weeks. Nine pregnancies were classified as stage III, and ten as stage IV. The mean gestational age at fetoscopic laser ablation was 22.0 (range: 19.0-26.0) weeks. There was no statistical difference in gestational age at the time of the procedure between patients with TTTS stage III (mean: 21.0; range: 20.0-25.0) and those with stage IV (mean: 22.0; range: 19.0-26.0; p=0.38). The number of anastomoses coagulated per procedure varied from 7 to 13 and was similar in both groups (p=0.42). The placenta was posterior in 10/19 (52.6%) pregnancies and anterior in 9/19 (47.4%). In the present study, a second fetoscopic laser coagulation was not required for any of the cases. There were no serious maternal complications during or after fetoscopy. There was no need for blood transfusion, laparotomy or admission to an intensive care unit.
Preterm premature rupture of the membranes (PPROM) occurred in 2/19 (10.5%) pregnancies (one was a TTTS stage III patient and the other was stage IV). In the first case, PPROM occurred two weeks after the procedure, which was performed at 24 weeks of gestation. At 26 weeks, the patient delivered vaginally and both twins died on the second day of life. A second patient with stage III TTTS underwent fetoscopic laser therapy at 25 weeks. PPROM occurred seven weeks after fetoscopic laser therapy. The patient delivered one baby who is currently healthy (the donor twin died two days after laser therapy).
Recurrence of polyhydramnios in the recipient's amniotic sac occurred in 3/19 (15.8%) pregnancies in which both twins survived after fetoscopic laser photocoagulation. In one patient, polyhydramnios recurred eight weeks after the procedure, and two amnioreductions were performed. The donor, who had already exhibited ventriculomegaly before the laser procedure, died in utero at 30 weeks of gestation. A Caesarean section was performed at 32 weeks; the recipient is currently healthy. In another patient, recurrence of polyhydramnios was observed four weeks after fetoscopic laser coagulation, and three amnioreductions were performed; the donor died in utero at 29 weeks. A Caesarean section was performed because of fetal distress and meconium at 31 weeks. The recipient died two days after birth. In a third patient, recurrent polyhydramnios was diagnosed three weeks after the procedure and three amnioreductions were performed. In this patient, tocolytic medication (beta-agonist) was used continuously from 22 to 26 weeks, and a Caesarean section was performed at 26 weeks of gestation. However, the recipient died one day after birth and the donor one week later.
Spontaneous According to the Quintero stages, there was a tendency for increased perinatal survival for stage III TTTS as compared to stage IV cases; however this difference did not reach statistical significance (Table 1). There was no cerebral morbidity among the 17 babies that survived.

DISCUSSION
This study presents our initial institutional experience with fetoscopic laser photocoagulation for the treatment of severe TTTS using a smaller diameter cannula and fetoscope than has been utilized in previous reports. Although the results presented here were obtained during our initial experience and represent elements of a learning curve, they are encouraging since they are similar to those reported from experienced referral centers in the United States and Europe. [19][20][21][22][23][24][25] Fetoscopic laser photocoagulation is usually performed using endoscopes from 1.2 mm to 3.3 mm in diameter that directly visualize the vessels on the placental surface. Once these inter-twin communicating vessels are identified, they are photocoagulated using laser energy. In our study, we used a smaller fetoscope and cannula of 1.0 mm and 2.2 mm, respectively. To the best of our knowledge, this is the first report in which this less invasive technique was performed in all cases and even at gestational ages of longer than 21 weeks. One advantage of using a narrower cannula and endoscope might be the lower risk for premature rupture of the membranes and preterm labor. Additionally, the narrower apparatus might reduce maternal discomfort during procedures performed with local skin anesthesia. For these reasons, we decided to try this less invasive technique. However, several disadvantages of using a narrower and shorter endoscope have been suggested, including lower image quality, which was not observed in our study, and limited assessment of the deepest fetal or placental structures. In severe TTTS, this limitation is of particular concern when the placenta is posteriorly located and a severe polyhydramnios is present. In this situation, a slight amnioreduction was performed to reduce the distance between the tip of the endoscope and the placenta, thereby allowing assessment of superficial placental structures with the endoscope. Thus, placental superficial anastomoses were clearly identified in all cases in the present study.
Many studies that assess this type of treatment, including a recent meta-analysis, 24,25 do not classify the severity of TTTS. However, it seems that laser therapy is superior to amnioreduction for stages II through IV. [19][20][21][22][23][24][25][26][27][28][29] The optimal treatment for Stage I disease has not been determined. O'Donoghue et al. 30 reported their observational experience for 46 pregnancies with stage I TTTS and found that the disease remained stable or regressed in 69.6% of cases. Survival rates were superior when compared to cases that progressed to at least stage III (30.4%). However, a factor that could predict the progression of the disease was not identified. Huber et al. 31 reported that even in cases of stage I TTTS, laser therapy is associated with improved perinatal outcomes.
We only applied our fetoscopic laser protocol to severe cases for two reasons. First, it is preferable to limit a new therapeutic option to only the most severe cases while an institution's healthcare workers are still becoming familiar with the new procedure. This logic is supported by the literature -indeed, laser therapy was initially only performed for stages II through IV. Many investigators have recently suggested that fetoscopic laser therapy might be associated with improved perinatal outcomes even for stage I patients; 31 in fact, it appears that the best results are achieved for stages I and II. The second reason that we only included TTTS stages III and IV was the late diagnosis and referral to our unit; these factors probably explain the high frequency of stage IV disease in our series as compared to other published reports.
Our results are very similar to recent reports for stage III and IV patients ( Table 2). For stage III, survival of at least one baby and both twins has been reported to range between 76.2% and 82.5% and between 19.1% and 53.8%, respectively. 19,[31][32][33] This compares to the rates of 88.9% and 33.3%, respectively, observed in the present study. For stage Our results are encouraging since they were obtained while our caregiver teams were still on the learning curve for this new procedure. The main problem in our series was that patients were referred too late, and thus presented with more severe complications. Although terminations of pregnancy and selective reductions have been reported as management options for severe TTTS in some series, termination was not performed in any of our cases. Obstetric complications such as PPROM and spontaneous preterm labor occurred with similar frequencies to those described in literature. 29,34 In conclusion, our initial institutional experience using a narrower endoscope for fetoscopic laser photocoagulation treatment of severe TTTS can be considered encouraging since we observed similar rates of obstetric complications and perinatal survival to those reported in literature. Therefore, we conclude that narrower and more delicate instruments can be used for endoscopic laser therapy in severe TTTS.

ACKNOWLEDGEMENT
We would like to thank Prof. Kenneth J. Moise Jr. from Texas Children's Fetal Center for the important revision of the present manuscript.