Objective
Residual anastomoses after fetoscopic laser surgery for twin-to-twin transfusion syndrome (TTTS) may lead to severe postoperative complications, including recurrent TTTS and twin anemia-polycythemia sequence (TAPS). A novel technique (Solomon technique) using laser coagulation of the entire vascular equator was recently investigated in a randomized controlled trial (Solomon trial) and compared with the Standard selective laser technique. The aim of this secondary analysis was to evaluate the occurrence and characteristics of residual anastomoses in placentas included in the Solomon trial.
Study Design
International multicenter randomized controlled trial in TTTS, randomized 1:1 ratio to either the Solomon laser technique or Standard laser technique. At time of laser, surgeons recorded whether they considered the procedure to be complete. Placental dye injection was performed after birth in the participating centers to evaluate the presence of residual anastomoses.
Results
A total of 151 placentas were included in the study. The percentage of placentas with residual anastomoses in the Solomon group and Standard group was 19% (14/74) and 34% (26/77), respectively ( P = .04). The percentage of placentas with residual anastomoses in the subgroup of cases where the procedure was recorded as complete was 8/65 (12%) and 22/69 (32%) in the Solomon group and Standard group, respectively ( P < .01).
Conclusion
The Solomon laser technique reduces the risk of residual anastomoses. However, careful follow-up remains essential also after the Solomon technique, as complete dichorionization is not always achieved.
Twin-twin transfusion syndrome (TTTS) occurs in 10% of monochorionic twins and is caused by imbalanced blood flow through placental vascular anastomoses. The best treatment for TTTS is fetoscopic laser coagulation of the anastomoses, which is associated with survival rates of both fetuses of 67%. The goal of fetoscopic laser surgery is to coagulate all vascular anastomoses. However, intertwin vascular connections may remain patent in up to 33% of TTTS cases. These residual anastomoses can cause severe postoperative complications such as twin anemia-polycythemia sequence (TAPS) in 13-16% or recurrent TTTS in 7-14% of cases in which both babies survive.
To minimize the occurrence of residual anastomoses and their complications, we investigated, in a randomized controlled trial, a modified fetoscopic laser surgery technique called the ‘Solomon technique.’ The aim of this technique is to draw a coagulation line along the entire vascular equator to reduce the risk of missing intertwin vascular anastomoses, in particular the poorly visualized small anastomoses. In the first analysis of the Solomon study, we focused on the perinatal outcome and showed a significant improvement in clinical outcome after the Solomon technique. The aim of this second analysis was to perform a detailed analysis of the placentas that were included in the Solomon study and to determine the occurrence and characteristics of residual anastomoses. In addition, we performed a subanalysis of all cases in which the surgeon reported that the procedure was technically complete.
Materials and Methods
Study design
The Solomon trial was an open-label, randomized, controlled trial that was performed in 5 European tertiary referral centers: University Hospitals KU Leuven (Belgium), University Hospital of Strasbourg (France), Birmingham Women’s Hospital, University of Birmingham, Birmingham (UK), Buzzi Hospital Milan (Italy), and Leiden University Medical Centre (The Netherlands). The study was approved by the Ethics committee of the Leiden University Medical Centre (MEC P07.261) and each center’s respective Institutional Review Board. The trial was registered with the Dutch trial registry, number NTR 1245. The background of the trial, methods, and baseline characteristics have been reported previously. In brief, the trial included 274 patients who were assigned randomly to the Solomon technique or standard technique. All TTTS cases that were included in the Solomon trial were eligible for this study, except cases that were treated in Birmingham. These cases (n = 25) were excluded from the current study because placentas were not injected routinely. Exclusion criteria were placenta maceration after intrauterine death with placentas with disrupted architecture as a result of the delivery process or when placentas were placed in formalin. In case fetal death occurred and the time period between fetal death and birth was within a week, the placentas were injected. Placentas were sent and injected in the participating centers of this trial. All other placentas were included in this study and injected with colored dye according to a specific technique reported later.
Placenta injection protocol
Placental storage and injection were performed according to previously published reports. In brief, after birth, placentas were stored in a plastic bowl at a storage temperature of 4°C (without being frozen or fixed in formalin) and injected within 1 week. Before injection, the placenta was washed with warm water, and amnions were removed for better visualization of the vascular anastomoses. The umbilical vein and at least 1 artery of each cord were cannulated. Syringes with 4 different colored dyes were connected to the cannulas, and the dye was gently injected into the placental vessels. A measuring tape was placed on the placenta, and digital high-resolution pictures were taken perpendicular to the placental surface. The following placental characteristics were recorded: number, localization, size, and type of residual anastomoses. Measurements of the size and localization of the anastomoses were performed with Image J 1.45s equipment and software (ImageJ; National Institutes of Health). The placental injections and subsequent evaluation of residual anastomoses could not be blinded because it is obvious from observing the placental surface which technique was used. In case of arteriovenous anastomoses, the caliber of the artery was measured. After measuring the total length of the vascular equator, we calculated its radius by dividing the length of the vascular equator into 2 parts. The localization of residual anastomoses was recorded as the ratio of the distance and radius (distance/radius), as previously reported. In case the residual anastomoses were detected during fetoscopic reintervention (because of TAPS or recurrent TTTS), these were analyzed in the group with residual anastomoses.
Primary and secondary outcome
The primary outcome of the Solomon trial was based on the short-term clinical outcome and included the presence of at least 1 of the 4 following items: TAPS, recurrent TTTS, perinatal death, or severe neonatal morbidity. One of the secondary outcomes of the Solomon trial was the incidence of residual anastomoses. In this placental study, we analyzed the type, size, and localization of residual anastomoses after colored dye injection. Comparison between the Solomon group and the standard group was performed in the total group of injected placentas, and in the subgroup of placentas from pregnancies in which the fetoscopic laser surgery was recorded as complete according to the surgeon’s opinion directly after the laser intervention. This subgroup analysis was performed to determine the impact of the surgeon’s opinion on the final result after fetoscopic laser surgery and to determine whether this could be useful to direct postoperative management.
We defined TTTS according to the Eurofoetus criteria, with a cut-off at a deepest vertical pocket of amniotic fluid in the donor at ≤2 cm; in addition, we used a cut-off for the deepest vertical pocket in the recipient of ≥8 cm within the first 20 weeks of gestation or ≥10 cm after gestational week 20. The definition of recurrent TTTS was based on the same parameters that were used to define TTTS. Recurrent TTTS included cases of reversal of TTTS. The presence or absence of TAPS was identified with the use of previously published criteria. In brief, antenatal TAPS was defined as present when Doppler ultrasound examination revealed an increase in middle cerebral artery–peak systolic velocity (MCA-PSV) of >1.5 multiples of the median in 1 fetus that coincided with a decrease in MCA-PSV of <0.8 multiples of the median in the cotwin. Postnatal TAPS was defined as both an intertwin hemoglobin difference of ≥8 g/dL at birth and at least 1 of the following occurrences: reticulocytosis in the donor with an intertwin reticulocyte count ratio >1.7 and/or the presence of only small (<1 mm in diameter) residual anastomosis that was seen at the time of postnatal placental injection studies. Severe neonatal morbidity was defined as the presence of at least 1 of the following occurrences: chronic lung disease (defined as oxygen dependency at 36 weeks of gestation), patent ductus arteriosus that required medical therapy or surgical closure, necrotizing enterocolitis grade ≥2, retinopathy of prematurity stage III or higher, ischemic limb injury, amniotic band syndrome, or severe cerebral injury. Severe cerebral injury includes at least 1 of the following occurrences: intraventricular hemorrhage grade III or higher, cystic periventricular leukomalacia grade II or higher, ventricular dilation of >97th percentile, porencephalic or parenchymal cysts, or other severe cerebral lesions that are associated with adverse neurological outcome. Neonatal follow-up evaluation was done by the treating neonatalogist. Length of follow-up time was until term age or at discharge (whichever came first); neonatal outcome in this study only included short-term outcome.
Statistical analysis
Continuous variables are reported as the mean ± standard deviation; group differences were compared by the Student t test. Proportions were compared with the chi-square test or the Fisher exact test, where appropriate. Differences with a probability value of < .05 were considered to be statistically significant. All analyses per fetus or neonate were performed with the use of the generalized estimated equation module to account for the effect that observations between co-twins are not independent. All statistical data were analyzed with SPSS software (version 20.0; IBM, Armonk, NY).
Results
A total of 247 placentas were eligible for this study ( Figure 1 ). We excluded 65 placentas because of maceration after intrauterine fetal death of 1 or both twins (n = 41), damage (n = 23), or placement in formalin (n = 1). In cases in which the placentas were damaged, this was often due to manual removal with disintegration of morphologic condition. Of the 41 cases that were excluded because of fetal death, 2 cases were double deaths, and 39 cases were single death. In one case, double death occurred within one week; in the other case, fetal demise occurred within a week after laser and the co-twin died more than a week after laser. Twenty-four of 39 of the single deaths (62%) occurred within 1 week after laser surgery, and 15 of 39 single deaths (38%) occurred more than a week after laser. Data on fetal condition before fetal death were not recorded. Finally, 31 eligible placentas were lost. This mainly occurred when patients delivered in referring hospitals. Two main reasons for delivering at a referral hospital were spontaneous premature delivery in which the patients could not be transferred to the treatment center or in cases with good recovery (normalization of amniotic fluid in both sacs and MCA-PSV Doppler measurements in both twins) in combination with the request of the patient to go back to the referral center (for logistic reasons). In these hospitals, placental injection studies were not a standard procedure, and placentas sometimes were discarded or accidentally fixed for routine pathologic evaluation. Gestational age at birth and the incidence of TAPS or recurrent TTTS was similar in the excluded group because of placental loss compared with the group of placentas that were included in the study ( Table 1 ).
| Variable | Total included placentas (n = 151) | Total lost placentas (n = 31) | P value |
|---|---|---|---|
| Gestational age at birth, wk a, b, c | 32 ± 3 | 32 ± 3 | .42 |
| Twin anemia polycythemia sequence, n (%) | 20 (13) | 2 (7) | .38 |
| Recurrent twin-twin transfusion syndrome, n (%) | 5 (3) | 1 (3) | 1.0 |
| Twin anemia polycythemia sequence or recurrent twin-twin transfusion syndrome, n (%) | 24 (16) | 3 (10) | .58 |
| Perinatal survival, n/N (%) c | 257/302 (85) | 49/62 (79) | .36 |
| Severe neonatal morbidity, n/N (%) c, d | 31/275 (11) | 5/53 (9) | .68 |
c Results were measured per fetus with the use of the Generalized Estimated Equation module
d Severe neonatal morbidity was measured per live born neonate.
Complete placental dye injection was performed in 151 placentas: 74 placentas (49%) in the Solomon group and 77 placentas (51%) in the standard group. Of the injected placentas, 19 placentas were after fetal death: in 9 double fetal deaths (47%), the placentas were injected; in the remaining 10 placentas (53%), the placentas could be injected after fetal death of the cotwin. The laser procedure was recorded by the surgeons as complete in 65 of 74 cases (88%) in the Solomon group and in 69 of 77 cases (90%) in the standard treatment group. There were no differences in baseline characteristics between the 2 study groups with respect to gestational age at fetoscopy, placenta localization, and Quintero stage ( Table 2 ).
| Characteristic | Solomon (n = 74) | Standard (n = 77) | P value |
|---|---|---|---|
| Gestational age at laser, wk a | 20 ± 2.6 | 20 ± 2.7 | .57 |
| Location of placenta, n (%) | .20 | ||
| Anterior | 27 (37) | 36 (47) | |
| Posterior | 47 (64) | 41 (53) | |
| Quintero stage, n (%) | .26 | ||
| I | 15 (20) | 17 (22) | |
| II | 27 (37) | 20 (26) | |
| III | 31 (42) | 35 (46) | |
| IV | 1 (1) | 5 (7) | |
| Laser complete (opinion surgeon), n (%) | 65 (88) | 69 (90) | .73 |
A significant reduction of residual anastomoses was seen after the use of the Solomon technique. Residual anastomoses were detected in 19% of placentas (14/74) in the Solomon group compared with 34% of placentas (26/77) in the standard group ( P = .04). In the subgroup of cases in which laser surgery was recorded as complete by the surgeon, an even larger reduction of residual anastomoses was seen: 12% (8/65) in the Solomon group compared with 32% (22/69) in the standard group ( P < .01; Table 3 ). In 3 cases with recurrent TTTS or TAPS that required reintervention with laser surgery, residual anastomoses were detected at time of reintervention during fetoscopy. All 3 cases were treated initially with the standard technique and were analyzed in the group with residual anastomoses. Placental injection after birth in these 3 cases showed no residual anastomoses. Two placentas (3%) in the Solomon group had proximate cord insertions (distance, <5 cm) and laser surgery was incomplete (although they were stated to be complete by the surgeon), which resulted in various large residual anastomoses between the 2 cords. No placentas with proximate cord insertions were present in the standard group.
| Variable | Total | Laser complete (surgeon’s opinion) | ||||
|---|---|---|---|---|---|---|
| Solomon (n = 74) | Standard (n = 77) | P value | Solomon (n = 65) | Standard (n = 69) | P value | |
| Placentas with residual anastomoses, n (%) | 14 (19) | 26 (34) | .04 | 8 (12) | 22 (32) | < .01 |
| Overall residual anastomoses per placenta, n a | 2 (1–24) | 2 (1–8) | .94 | 2 (1–4) | 2 (1–5) | .90 |
| Diameter of residual anastomoses, mm b | 1.3 ± 1.8 | 0.8 ± 0.9 | .07 | 2.1 ± 3.0 | 0.9 ± 1.0 | .01 |
| Placentas with arteriovenous residual anastomoses, n (%) | 10 (71) | 21 (91) | .11 | 6 (75) | 17 (90) | .33 |
| Placentas with arterioarterial residual anastomoses, n (%) | 6 (43) | 4 (17) | .09 | 3 (38) | 2 (11) | .10 |
| Placentas with venovenous residual anastomoses, n (%) | 7 (50) | 4 (17) | .04 | 4 (50) | 3 (16) | .06 |
a Data are given as median (range)
The median number of residual anastomoses was similar in the Solomon and standard groups ( Table 3 ). In the subgroup of cases in which laser surgery was recorded as complete by the surgeon, the mean diameter of residual anastomoses was 2.1 ± 3.0 mm in the Solomon group vs 0.9 ± 1.0 mm in the standard group ( P = .01). The larger mean diameter of residual anastomoses in the Solomon group mainly was due to the 2 placentas with proximate cord insertion. After analysis of the data without the 2 placentas with proximate cord insertions, the mean diameter of residual anastomoses in the Solomon and the standard groups was similar (1.4 ± 1.3 mm vs 0.9 ± 1.0 mm, respectively; P = .15). The localization of residual anastomoses was distributed evenly along the vascular equator. Placentas with residual anastomoses in the Solomon group where the surgeon stated to be complete were characterized by proximate cord insertion (n = 2), discontinuous line (n = 5), and Solomon line not along the vascular equator (n = 1). Figure 2 shows a placenta that was treated with the Solomon technique with residual anastomoses near the margin of the placenta that caused TAPS.
