Changes in sVEGFR-1 and sVEGFR-2 Levels Following Fetoscopic Laser Photocoagulation in Twin-to-Twin Transfusion Syndrome: Implications for Fetal demise Prediction.

Circulating angiogenic factors in monochorionic twin pregnancies complicated by twin-to-twin transfusion syndrome and selective intrauterine growth restriction

Guideline No. 440: Management of Monochorionic Twin Pregnancies

The roles of superficial anastomoses in twin-twin transfusion syndrome

Aim: This study was performed to evaluate maternal changes in laboratory characteristics after fetoscopic laser photocoagulation (FLP) for twin-to-twin transfusion syndrome (TTTS). Methods: A retrospective review was conducted among 30 women with monochorionic diamniotic twin pregnancy with TTTS who underwent FLP at 16–26 weeks of gestation. Maternal laboratory parameters were measured before and after FLP. Results: The pre-FLP mean hemoglobin level (10.0 g/dL), hematocrit level (30.0%), platelet count (229 × 10⁹/mL), fibrinogen level (461 mg/dL), and antithrombin activity (96.8%) decreased after FLP (8.5 g/dL, 25.5%, 204 × 10⁹/mL, 403 mg/dL, and 83.6%, respectively) and returned to normal spontaneously within 2 weeks (9.6 g/dL, 29.4%, 293 × 10⁹/mL, 460 mg/dL, and 102.4%, respectively). The D-dimer level before FLP (2.41 μg/mL) increased after FLP (4.28 μg/mL), and the elevated level was maintained for 2 weeks (3.24 μg/mL). The symptomatic venous thromboembolism (VTE) was not detected after FLP in any of the 30 patients. However, one woman had pulmonary embolism after subsequent cesarean section. Conclusion: Changes in maternal anemia and coagulation/fibrinolysis after FLP for TTTS returned to normal spontaneously within 2 weeks. Maternal elevation of D-dimer level after FLP might be a warning indicator of VTE.

Interleukin-4 and granulocyte-macrophage colony-stimulating factor mediates the upregulation of soluble vascular endothelial growth factor receptor-1 in RAW264.7 cells-a process in which p38 mitogen-activated protein kinase signaling has an important role.

Fetoscopic laser photocoagulation (FLP), a treatment option for twin-to-twin transfusion syndrome (TTTS) in monochorionic twin pregnancies, is currently the treatment of choice at our centre. We previously reported on our experience of FLP from June 2011 to March 2014. This paper audits our fetal surgery performance since then. 15 consecutive patients who underwent FLP for Stage II-III TTTS before 26 weeks of gestation from June 2011 to January 2017 were retrospectively reviewed, consisting of five cases from our initial experience and ten subsequent cases. Perioperative, perinatal and neonatal outcomes were analysed. Of 15 pregnancies, 10 (66.7%) and 5 (33.3%) were for Stage II and III TTTS respectively, with FLP performed at an earlier Quintero stage in the later cohort. Overall mean gestational ages at presentation, laser and delivery were comparable between the cohorts at 19.7 (15.4-24.3) weeks, 20.3 (16.3-25.0) weeks and 31.2 (27.6-37.0) weeks, respectively. 2 (13.3%) cases had intra-amniotic bleeding and 1 (6.7%) had iatrogenic septostomy. 1 (6.7%) case had persistent TTTS requiring repeat FLP, and another (6.7%) had preterm premature rupture of membranes at seven weeks post procedure. The overall perinatal survival rate was 21 (75.0%) out of 28 infants. One mother underwent termination of pregnancy for social reasons at 1.4 weeks post procedure. Double survival occurred in 8 (57.1%) out of 14 pregnancies, while 13 (92.9%) had at least one survivor. FLP requires a highly specialised team and tertiary neonatal facility. Continual training improves maternal and perinatal outcomes, ensuring comparable standards with international centres.

Aims: Fetoscopic laser surgery has been widely accepted of optimal treatment for Twin-Twin Transfusion Syndrome (TTTS) in monochorionic twin pregnancies. To avoid surgical complication and to improve the outcome, various techniques employed in our institution. The aim of our study is to assess the clinical outcomes of TTTS after laser surgery with combined various techniques. Methods: We performed 171 cases of fetoscopic laser surgery for TTTS from 2002 to 2011 in our institution. Various techniques employed in our studies to improve the learning of laser surgery and to achieve successful outcome were; (1) A very thorough mapping of vascular anastomoses before and after ablation; (2) Obliteration of arterio-venous anastomoses from donor to recipient should be done first, (3) Trocar assisted technique using gentle indent the trocar withdrawing the scope shortly, to ablate anastomoses easily, (4) A virtual line was drawn by laser at the hemodynamic equator to avoid residual anastomoses, and not to miss small anastomoses. Results: Laser photocoagulation was performed since 2002 in our institute, compiling 171 cases. Overall survival was 78% with 5% neonatal morbidity. Both twins survived for 64%, and the survival of one twin was 93%. The recurrent TTTS rate was 1%, and the residual vessel rate was 2%. Conclusion: A successful outcome for fetoscopic laser surgery is achievable and the outcome is improved in severe TTTS cases by these techniques.

The purpose of this study was to investigate the outcomes of fetoscopic laser photocoagulation (FLP) for twin-to-twin transfusion syndrome (TTTS) in Japan. The retrospective cohort study (2012-2018) was conducted in monochorionic twin pregnancies that underwent FLP for TTTS between 26 and 27 weeks from 2012 to 2018. The perioperative data, maternal complications, gestational age (GA) at delivery, neonatal complications, and survival of infants at 28 days of age were analyzed. At term-equivalent age, severe neurological complications were identified by imaging study. Of 644 patients, 28 (4.3%) underwent FLP between 26 and 27 weeks, and 26 were analyzed. FLP procedures were technically successful in all cases. There were no cases of major maternal complications after surgery. Preterm rupture of membranes occurred in 34.6% of cases, and the mean GA at delivery was 33.2 ± 3.1 weeks. The survival of both twins was found in 23 (88.4%) cases, and the perinatal survival rate of at least one twin at 28 days of age was 100%. Severe neurological complications were found in six (12.2%) cases out of 49. FLP for TTTS between 26 and 27 weeks provided a good prognosis and caused no major maternal complications. However, severe neurological findings were found in 12% of infants.

Twin-to-twin transfusion syndrome (TTTS) is the most common serious complication of monochorionic (MC) twin pregnancies, with perinatal mortality rates of up to 90% if untreated. This study aimed to review the perinatal and perioperative outcomes of MC twin pregnancies treated for TTTS by fetoscopic laser photocoagulation (FLP) since its introduction at KK Women's and Children's Hospital (KKH), Singapore, in 2011. This was a retrospective review of five consecutive patients who underwent FLP of placental anastomoses for TTTS at KKH from June 2011 to March 2014. FLP was offered to patients who were diagnosed with TTTS of at least Quintero Stage II before 26 weeks of gestation. The main outcome measures were perioperative complications and perinatal survival rates. Five sets of MC twin pregnancies underwent FLP during the study period - three pregnancies were diagnosed with Stage III TTTS and two pregnancies with Stage II TTTS. Median gestational ages at initial presentation, laser photocoagulation and delivery were 19 (range 17-20) weeks, 20 (range 19-23) weeks and 29 (range 28-34) weeks, respectively. One patient had bleeding into the amniotic cavity intraprocedurally. Overall, the perinatal survival rate, double-infant survival rate and survival rate for at least one twin were 60% (6/10 fetuses), 40% (2/5 twins) and 80% (4/5 twins), respectively. FLP is a feasible treatment for TTTS, with minimal maternal complications. Perinatal survival rates of this patient group that was managed at our centre were comparable to those of international centres.

Role of Soluble Vascular Endothelial Growth Factor Receptor-1 in the Vitreous in Proliferative Diabetic Retinopathy

Gestational age and Quintero staging as predictors of single fetal demise in twin-twin transfusion syndrome after fetoscopic laser photocoagulation: a systematic review and meta-analysis

Angiogenic factors play a role in human placentation and may be aberrant in severe twin-to-twin transfusion syndrome (TTTS). The aim of this study was to investigate the maternal plasma and amniotic fluid angiogenic factor and receptor concentrations in twin pregnancies complicated by TTTS and to evaluate the effects of fetoscopic laser ablation. A prospective cohort of monochorionic (MC) twins complicated by severe TTTS (n = 23) was studied between October 2006 and December 2007. A cohort of uncomplicated dichorionic (DC) (n = 12) and MC (n = 7) pregnancies were studied for comparison. Circulating angiogenic factors and their receptors were measured in the maternal plasma and the recipient twin's amniotic fluid by enzyme-linked immunosorbent assay and/or FAST Quant human angiogenesis array. Plasma vascular endothelial growth factor (VEGF)-C concentrations were significantly lower in TTTS than in uncomplicated twin pregnancies (P < 0.0001). In contrast, plasma angiopoietin (Ang)-2 levels and the ratio of soluble vascular endothelial growth factor receptor-1 (sVEGFR-1) to placental growth factor (PlGF) levels were significantly increased in TTTS (P < 0.01). Plasma VEGF-D was significantly increased in advanced stage TTTS (Stage III/IV cohort; P < 0.01). This was independent of fetal size, amniotic fluid volumes or the number of apparent placental arteriovenous anastomoses. In TTTS pregnancies, amniotic fluid VEGF-C, VEGF-A, Ang-1 and the sVEGFR-1/PlGF ratio were increased compared to paired maternal plasma concentrations (P < 0.0001) while amniotic fluid concentrations of PlGF, Ang-2 and soluble tyrosine kinase with immunoglobulin-like/epidermal growth factor-like domains 2 (sTie-2) were significantly lower than plasma concentrations (P < 0.0001). No significant association between maternal plasma and amniotic fluid concentrations of angiogenic factors was noted. Plasma PlGF was transiently decreased after fetoscopic laser ablation, returning to baseline by 1 week (P = 0.0314). Fetoscopic laser ablation also affected plasma sVEGFR-1/PlGF ratio with a transient increase after therapy, followed by a significant reduction to below basal concentrations by 1 week (P = 0.0102). Only VEGF-D was significantly different (+8.3%; P = 0.0155) in amniotic fluid immediately after the completion of fetoscopic laser ablation. Maternal angiogenic activity is decreased in severe TTTS, with an increased sVEGFR-1/PlGF ratio and concentrations of Ang-2 and VEGF-D in the maternal plasma compared to uncomplicated MC twin pregnancies. Maternal circulating PlGF concentrations decrease and the sVEGFR-1/PlGF ratio increases transiently in response to fetoscopic laser ablation, but in general the angiogenic factor and receptor concentrations studied are altered little by this therapy.

The diagnostic criteria for Quintero staging in twin-to-twin transfusion syndrome (TTTS) are not applicable in all cases of TTTS, such as those in which the symptoms overlap with other monochorionic twin complications such as selective intrauterine growth restriction (sIUGR). A 25-year-old woman, G1P0A0, at 22-24 weeks' gestational age was diagnosed with TTTS, with no outstanding history of medication use during pregnancy, and no family history of genetic disorder or twin pregnancy. In the donor twin, persistently absent end-diastolic flow in the umbilical artery was observed using Doppler velocimetry. Polyhydramnios was observed in the recipient twins. The fetal weight discordance between the twins was 39%. After 2 weeks of follow-up, the authors performed fetoscopic laser photocoagulation and successfully ablated five vascular anastomoses and amnioreduction by 2.5l. Five days after the laser surgery, the patient developed amniotic fluid leakage, and an amniopatch was performed. The authors did the caesarean section at 34 weeks because of severe preeclampsia, the donor and recipient birth weights were 1,120g and 1,837g, respectively (weight discordance 39%). The APGAR scores were 3/4 and 6/8, respectively. The donor twin died 6 days after delivery due to respiratory failure, and the recipient twin survived. Neonatal echocardiography of the surviving twin showed no tricuspid regurgitation. No long-term follow-up was performed. The traditional diagnostic criteria for TTTS stage 3 were not met and overlapped with the diagnostic criteria for sIUGR type 2. This is the first procedure reported in Indonesia for atypical TTTS with the outcome, one twin survived. Some TTTS cases do not meet traditional diagnostic criteria and overlap with other monochorionic twin complications.

ISUOG Practice Guidelines: role of ultrasound in twin pregnancy.

To assess the hemodynamics of twin-to-twin transfusion syndrome (TTTS), we measured the intraventricular pressure difference (IVPD), a sensitive marker of myocardial diastolic function, using fetal echocardiography. We included 28 monochorionic diamniotic (MD) twins diagnosed with TTTS who underwent fetoscopic laser photocoagulation (FLP) between 2018 and 2022. Color M-mode Doppler images of both cardiac ventricles were obtained before and after FLP. According to this evaluation, the IVPDs were divided into three groups; those with total, basal, and mid-apical IVPD. Of the 28 twins, 21 were available for analysis (including eight, eight, three, and two cases in stages Quintero Ⅰ, Ⅱ, Ⅲd, and Ⅲr, respectively). Comparing the pre and postFLP results, significant increases in total and mid-apical IVPD in the left ventricle (LV) of recipient twins were noted (total and mid-apical IVPD: p=0.026 and 0.013, respectively). In the LV of the donor twins, all IVPDs were significantly increased after FLP (total, basal, and mid-apical IVPD: p=0.003, 0.001, and 0.022, respectively). In addition, comparisons between the donor and recipient groups did not show significant differences in either ventricle before FLP. IVPD detected subtle hemodynamics changes, such as volume overload and diastolic dysfunction in TTTS before and after FLP. Therefore, IVPD may be a useful marker for monitoring myocardial diastolic function in TTTS.