BACKGROUND: Twin-twin transfusion syndrome (TTTS) affects 10-15% of monochorionic twin pregnancies. Without treatment, their mortality rates would be considerable. There are differences in survival rate between different therapeutic modalities. This study aims to compare the cost-effectiveness of Fetoscopic laser versus amnioreduction, septostomy, and expected management in the treatment of twin-to-twin transfusion syndrome (TTTS).
METHODS: This is a cost-effectiveness analysis of the treatment strategies in patients with TTTS. A decision tree model was used to estimate the clinical and economic outcomes with a pregnancy period time horizon. Medical direct costs were extracted in a quantitative study, and survival rates were determined as effectiveness measures based on a review. A probabilistic sensitivity analysis was used to measure the effects of uncertainty in the model parameters. The TreeAge, Excel and R software were used for analyzing data.
RESULTS: In the first phase, 75 studies were included in the review. Based on the meta-analysis, a total of 7183 women treated with Fetoscopic laser, the perinatal survival of at least one twin-based pregnancy was 69%. In the second phase, the results showed that expected management and amnioreduction have the lowest (791.6$) and highest cost (2020.8$), respectively. Based on the decision model analysis, expected management had the lowest cost ($791.67) and the highest rate in at least one survival (89%), it was used only in early stages of TTTS. Fetoscopic laser surgery, with the mean cost 871.46$ and an overall survival rate of 0.69 considered the most cost-effectiveness strategy in other stages of TTTS.
CONCLUSIONS: Our model found Fetoscopic laser surgery in all stages of TTTS to be the most cost-effective therapy for patients with TTTS. Fetoscopic laser surgery thus should be considered a reasonable treatment option for TTTS.

Background: Most previous studies evaluated outcomes of twin-twin transfusion syndrome (TTTS) without considering the coexistence of selective fetal growth restriction (sFGR). The objectives of this study were to compare twin survival and pregnancy complications after laser therapy of TTTS with and without sFGR. Methods: For this purpose, a retrospective cohort study including 98 monochorionic diamniotic twins and three dichorionic triamniotic triplets treated in a single tertiary center was conducted. Results: Overall, 46 twins had selective fetal growth restriction (26 type I, 13 type II, 7 type III). At birth, donor survival (61% vs. 91%), double survival (57% vs. 82%), and overall survival (75% vs. 88%) were significantly lower in the group with coexistent sFGR. Recipient survival (89% vs. 86%), miscarriage (7% vs. 2%), PPROM < 32 weeks (48% vs. 29%), and preterm delivery < 32 weeks (52% vs. 45%) were not significantly higher in the group with coexistent sFGR. Donor twins with sFGR type I (69% vs. 91%) and types II-III (50% vs. 91%) showed significantly lower survival than those without sFGR. Multivariate regression analysis identified sFGR and its subtypes as independent predictors of donor demise. Conclusions: the coexistence of sFGR in TTTS pregnancies was associated with poor donor outcomes and is probably the most important predictor of donor survival.

BACKGROUND: Perforation of the intertwin membrane can occur as a complication of fetoscopic laser surgery for twin-twin transfusion syndrome (TTTS). Data on the occurrence and the risk of subsequent cord entanglement are limited. The objective of this study was to assess the prevalence, risk factors and outcome of intertwin membrane perforation, and cord entanglement after laser surgery for TTTS.
METHODS: In this multicenter retrospective study, we included all TTTS pregnancies treated with laser surgery in two fetal therapy centers, Shanghai (China) and Leiden (the Netherlands) between 2002 and 2020. We evaluated the occurrence of intertwin membrane perforation and cord entanglement after laser, based on routine fortnightly ultrasound examination and investigated the risk factors and the association with adverse short- and long-term outcomes.
RESULTS: Perforation of the intertwin membrane occurred in 118 (16%) of the 761 TTTS pregnancies treated with laser surgery and was followed by cord entanglement in 21% (25/118). Perforation of the intertwin membrane was associated with higher laser power settings, 45.8 Watt versus 42.2 Watt (p = 0.029) and a second fetal surgery procedure 17% versus 6% (p < 0.001). The group with intertwin membrane perforation had a higher rate of caesarean section (77% vs. 31%, p < 0.001) and a lower gestational age at birth (30.7 vs. 33.3 weeks of gestation, p < 0.001) compared to the group with an intact intertwin membrane. Severe cerebral injury occurred more often in the group with intertwin membrane perforation, 9% (17/185) versus 5% (42/930), respectively (p = 0.019). Neurodevelopmental outcome at 2 years of age was similar between the groups with and without perforation of the intertwin membrane and between the subgroups with and without cord entanglement.
CONCLUSIONS: Perforation of the intertwin membrane after laser occurred in 16% of TTTS cases treated with laser and led to cord entanglement in at least 1 in 5 cases. Intertwin membrane perforation was associated with a lower gestational age at birth and a higher rate of severe cerebral injury in surviving neonates.

Twin-twin transfusion syndrome (TTTS) is characterized by unequal hemodynamics between the twins. We aimed to assess preoperatively the difference in umbilical vein flow (UVF) between the recipient and donor monochorionic diamniotic twins and evaluate the change in UVF following laser surgery in both twins.
This was a retrospective cohort study of differences in UVF that occurred following laser surgical treatment of TTTS. Sonographic assessment of the umbilical vein before and 24 h after fetoscopic laser surgery for TTTS was performed. Umbilical vein diameter and time-averaged maximum velocity were measured, and UVF per kg (UVF/kg) was converted into a Z-score by a calculator created using gestational age as an independent variable. Z-score values were converted into centiles, which were evaluated statistically. Median differences in UVF/kg centile values were adjusted for TTTS stage and presence of arterioarterial anastomoses.
The study population consisted of 363 TTTS patients. The adjusted preoperative median difference in UVF/kg centile between the recipient vs donor twin was 17.9% (-17.1% to 57.6%), P < 0.0001. The adjusted median difference in UVF/kg centile between the postoperative vs preoperative period among recipients was 2.2% (-10.8% to 13.8%), P < 0.0001, while the adjusted median difference among donors was 27.3% (8.2%-34.6%), P < 0.0001.
The preoperative difference in UVF between the recipient and donor twins confirms the pathophysiology of TTTS. Postoperatively, the substantial increase in UVF of the donor twin and the relatively small increase in UVF of the recipient twin confirm that ablation of the vascular communications resulted in rapid improvement in perfusion of the donor twin. © 2022 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

BACKGROUND: Single fetal demise after intervention for twin-twin transfusion syndrome is a relatively common complication and is often devastating for the patients.
OBJECTIVE: This meta-analysis aimed to evaluate the risk of single fetal demise based on gestational age and Quintero staging at the time of interventions in twin-to-twin transfusion syndrome after fetoscopic laser photocoagulation.
METHODS: Systematic search was performed in PubMed, Web of Science, and Scopus from inception to August 2021. The primary outcome was to compare the incidence of fetal demise between low (I and II) and high (III and IV) twin-to-twin transfusion syndrome Quintero stages. The rate of donor and recipient fetal demise in each stage was compared with that in stage I. Gestational age at fetoscopic laser photocoagulation was compared between surviving fetuses and fetuses that died.
RESULTS: A total of 10 studies (4031 fetuses with twin-to-twin transfusion syndrome) were included in this review. Donor demise was associated with high Quintero stages compared with surviving donors (odds ratio, 2.42; 95% confidence interval, 1.78-3.29; P<.001; I2 , 0%). Recipient fetal demise had a trend for higher Quintero stage compared with surviving recipients, but the analysis did not achieve statistical significance. Pregnancies with donor demise had lower gestational at the time of fetoscopic laser photocoagulation (mean difference, -0.56; 95% confidence interval, -0.93 to -0.18; P=.003; I2 , 36%), whereas pregnancies complicated by recipient demise had similar gestational at time of fetoscopic laser photocoagulation compared with those without demise.
CONCLUSIONS: Demise of the donor fetus was significantly increased after fetoscopic laser photocoagulation for higher stages compared with lower ones. Lower gestational age at the time of fetoscopic laser photocoagulation was associated with an increased risk of single fetal demise in twin-to-twin transfusion syndrome. This was attributed to increased donor demise but not recipient death.

Selective fetoscopic laser photocoagulation (SFLP) for twin-to-twin transfusion syndrome (TTTS) is challenging for new surgeons at the start of their learning curve. We described an approach utilising telementoring and team-based training to facilitate rapid attainment of the skills required for safe and efficient practice with a limited caseload.
We conducted a prospective observational study of SFLP performed by the novice primary surgical team in three stages: under direct on-site supervision from an expert mentor (Group 1), with remote tele-guidance from that mentor (Group 2) and independently (Group 3), at an academic tertiary hospital in Singapore. The primary team undertook regular training on high-fidelity tissue models to accelerate skills acquisition and complement the surgical performance.
9 patients diagnosed with Stage 2 TTTS were assessed for procedural characteristics, surgical outcomes and perinatal survival following SFLP. There were no significant differences in operative duration, anastomoses ablated, gestational age or birth weight at delivery. The complications observed were: recurrent TTTS (22.2% of pregnancies), twin anaemia polycythaemia sequence (33.3%), preterm prelabour membrane rupture (22.2%) and delivery at < 32 weeks (44.4%). ≥ 1 twin was live-born in 88.9% of cases, while postnatal survival to six months of ≥ 1 twin occurred in 77.8% of cases.
Systematic mentoring and specialised skills training are useful in aiding new surgeons to negotiate the steep learning curve and achieve good outcomes at the start of a new practice, particularly in the setting of low patient numbers. This is best paired with dedicated model training to achieve and maintain surgical dexterity for this complex procedure.

Objectives: To investigate metabolomic perturbations caused by twin-twin transfusion syndrome, metabolic changes associated with fetoscopic laser coagulation in both placental tissue and cord plasma, and to investigate differential metabolites pertinent to varying fetal outcomes, including hemodynamic status, birth weight, and cardiac function, of live-born babies. Methods: Placental tissue and cord plasma samples from normal term or uncomplicated preterm-born monochorionic twins and those complicated by twin-twin transfusion syndrome treated with or without fetoscopic laser coagulation were analyzed by high-performance liquid chromatography metabolomic profiling. Sixteen comparisons of different co-twin groups were performed. Partial least squares-discriminant analysis, metabolic pathway analysis, biomarker analysis, and Spearman\'s correlation analysis were conducted based on differential metabolites used to determine potential biomarkers in different comparisons and metabolites that are pertinent to neonatal birth weight and left ventricular ejection fraction. Results: These metabolomic investigations showed that the cord plasma metabolome has a better performance in discriminating fetuses among different hemodynamic groups than placental tissue. The metabolic alteration of twin-twin transfusion syndrome in these two types of samples centers on fatty acid and lipid metabolism. The fetoscopic laser coagulation procedure improves the metabolomic change brought by this syndrome, making the metabolomes of the treated group less distinguishable from those of the control and preterm birth groups. Certain compounds, especially lipids and lipid-like molecules, are noted to be potential biomarkers of this morbid disease and pertinent to neonatal birth weight and ejection fraction. Conclusions: Fetoscopic laser coagulation can ameliorate the metabolomic alteration caused by twin-twin transfusion syndrome in placental tissue and cord plasma, which are involved mainly in fatty acid and lipid-like molecule metabolism. Certain lipids and lipid-like molecules are helpful in differentiating co-twins of different hemodynamic statuses and are significantly correlated with neonatal birth weight or ejection fraction.

UNASSIGNED: To evaluate the surgery outcomes of fetoscopic laser ablation (FLA) for selective umbilical cord in treating twin-twin transfusion syndrome (TTTS) with special conditions and neonatal outcomes post-operation.
UNASSIGNED: A prospective study, 21 monochorionic diamniotic (MCDA) twins diagnosed with TTTS stage II-IV according to Quintero classification from 16 to 26 weeks of gestation, among that, 12 cases of TTTS stage II with selective intrauterine growth restriction (sIUGR), 6 cases of TTTS stage II with proximate cord insertions, 3 cases of TTTS stage IV underwent fetoscopic laser ablation for the selective fetal reduction at Hanoi Obstetrics and Gynecology Hospital from September 2019 to July 2021. Complications and surgical outcomes were noted. Prenatal care was carried out every 2 weeks post operation until birth. Newborn neurologic complications were assessed at birth, three months, and six months after birth using Denver II test and magnetic resonance imaging (MRI).
UNASSIGNED: The mean gestational age at operation was 20.30 weeks. The average operation duration was 39.52 minutes. No complications of operation, such as bleeding or infection, were recorded. The mean gestational age at birth was 34.70 ± 4.33 weeks, with a mean duration of 12.97 ± 6.87 weeks between intervention and delivery. The survival rate of newborns after the operation was 90.48%. There were two stillbirths (9.52%) within seven days after the operation. No short-term neurological complications have been reported with follow-up of the newborn to 6 months after birth.
UNASSIGNED: Our study showed that fetoscopic laser ablation of selected fetal reduction surgery for treatment of special conditions of TTTS had no complications of operation, high neonatal survival result (90.48%), no short-term neurological complications. This should be considered for TTTS in cases of indication.

Twin-twin transfusion syndrome (TTTS) is a rare but serious cause of fetal cardiomyopathy with poorly understood pathophysiology and challenging prognostication. This study sought a nonbiased, comprehensive assessment of amniotic fluid (AF) microRNAs from TTTS pregnancies and associations of these miRNAs with clinical characteristics. For the discovery cohort, AF from ten fetuses with severe TTTS cardiomyopathy were selected and compared to ten normal singleton AF. Array panels assessing 384 microRNAs were performed on the discovery cohort and controls. Using a stringent q < 0.0025, arrays identified 32 miRNAs with differential expression. Top three microRNAs were miR-99b, miR-370 and miR-375. Forty distinct TTTS subjects were selected for a validation cohort. RT-PCR targeted six differentially-expressed microRNAs in the discovery and validation cohorts. Expression differences by array were confirmed by RT-PCR with high fidelity. The ability of these miRNAs to predict clinical differences, such as cardiac findings and later demise, was evaluated on TTTS subjects. Down-regulation of miRNA-127-3p, miRNA-375-3p and miRNA-886 were associated with demise. Our results indicate AF microRNAs have potential as a diagnostic and prognostic biomarker in TTTS. The top microRNAs have previously demonstrated roles in angiogenesis, cardiomyocyte stress response and hypertrophy. Further studies of the mechanism of actions and potential targets is warranted.

OBJECTIVE: To investigate the neurodevelopmental outcome at age 2 and 5 years in survivors of twin-twin transfusion syndrome (TTTS) treated with fetoscopic laser surgery and born premature and/or small for gestational age.
METHODS: At 2 and 5 years of age, standardized neurologic, motor, and cognitive assessments were performed by a neonatologist, a pediatric physical therapist, and a psychologist. Behavior was assessed using a validated questionnaire completed by parents.
RESULTS: Neurodevelopmental assessment at both time points was available for 73 survivors of TTTS. Mild to moderate neurodevelopmental impairment (NDI) was detected in 34% of survivors (25 of 73) at 5 years, compared with 25% (18 of 73) at 2 years (P = .178). Severe NDI was observed in 12% (9 of 73) at 5 years and in 3% (2 of 73) at 2 years (P = .035). Mean cognitive score was lower at the 5-year follow-up (90.7 ± 12.3 vs 95.6 ± 13.1 at 2 years; P = .001), and more children were diagnosed with mild cognitive impairment at 5 years (29% vs 11% at 2 years; P = .007). When comparing individual outcomes at both time points, 35% (25 of 71) moved from a normal outcome or mild to moderate impairment at 2 years toward more severe impairment at 5 years.
CONCLUSIONS: A high rate of mild to moderate cognitive impairment and severe NDI at age 5 years was not identified at age 2 years. Our data highlight the importance of longitudinal follow-up of survivors of TTTS beyond age 2 years and emphasize the precautions that should be taken when diagnosing an absence of impairment before school age.