DOI: 10.1111/j.1471-0528.2007.01336.x Fetal medicine www.blackwellpublishing.com/bjog Severe twin–twin transfusion syndrome: outcome after fetoscopic laser ablation of the placental vascular equator AM Ierullo, AT Papageorghiou, A Bhide, N Fratelli, B Thilaganathan Fetal Medicine Unit, Department of Obstetrics and Gynaecology, St George’s Hospital NHS Trust, London, UK Correspondence: Dr B Thilaganathan, Fetal Medicine Unit, Department of Obstetrics and Gynaecology, 4th Floor, Lanesborough Wing, St George’s Hospital NHS Trust, Blackshaw Road, London SW17 0QT, UK. Email basky@pobox.com Accepted 3 January 2007. Setting Tertiary referral fetal medicine unit. average, four vessels were ablated during each procedure, with a mean operative time of 15 (range 5–25) minutes. None of the women required a repeat fetoscopic laser treatment for recurrence of the TTTS. There was at least one survivor in 74% (57/77) of pregnancies, and the overall survival rate was 57% (88/154). Population Women with pregnancies complicated by severe TTTS Conclusions Fetoscopic laser ablation is a safe and effective form (Quintero stage III or IV), before 26 weeks of gestation. of treatment in the management of severe TTTS. The technique of identifying the common villous district of the placenta by ultrasound and photocoagulating any vessels crossing the vascular equator appears to be an acceptable alternative to both the nonselective and highly selective methods described so far. This approach is associated with a short operating time, low likelihood of TTTS recurrence or fetal anaemia and with survival results that are equivalent to previously reported techniques. Objective To assess the safety and efficacy of a modified fetoscopic laser ablation technique for the management of severe twin–twin transfusion syndrome (TTTS) in a large series of pregnancies. Design Prospective cohort study. Methods Fetoscopic laser ablation of placental anastomoses was performed. The sonoendoscopic approach was used to identify the placental vascular equator and to photocoagulate crossing vessels. Main outcome measures Overall survival, fetal and perinatal mortalities, gestational age at delivery, birthweight, operating time and recurrence of TTTS. Results A total of 77 women underwent the procedure. The mean gestational age at treatment was 20 (range 16–26) weeks. On Keywords Fetoscopy, laser ablation, monochorionic, twins, TTTS. Please cite this paper as: Ierullo A, Papageorghiou A, Bhide A, Fratelli N, Thilaganathan B. Severe twin–twin transfusion syndrome: outcome after fetoscopic laser ablation of the placental vascular equator. BJOG 2007;114:689–693. Introduction Twin-to-twin transfusion syndrome (TTTS) is a recognised midtrimester complication occurring in up to 15% of monochorionic gestations.1 If left untreated, the mortality of this condition exceeds 90%, with significant neurological morbidity in 30–50% of surviving twins.2,3 The most well established treatment options for TTTS include serial amnioreduction and fetoscopic laser ablation of the placental vascular anastomoses. The reported survival rates for amnioreduction are 39–64% compared with 56–62% for fetoscopic laser ablation.4–7 Long-term neurodevelopmental morbidity rates for amnioreduction are 7–26%3,8–12 compared with 6–11% for laser ablation.13–15 In 2005, a systematic review confirmed the significant increase in survival rates and reduction in neurological morbidity with the use of laser ablation compared with amnioreduction in severe TTTS.16 However, laser ablation is a more complex technique and less readily available than amnioreduction. In the nonselective fetoscopic laser technique, all vessels crossing the intertwin membrane are photocoagulated.4 This approach is thought to be associated with higher fetal loss rates than the highly selective technique, where all vessels are followed systematically from the point they cross the intertwin membrane until it can be verified whether they are normal or resulting in an anastomoses with the co-twin.17 Although the highly selective technique may have a higher survival rate, it is a time-consuming operation, with an ª 2007 The Authors Journal compilation ª RCOG 2007 BJOG An International Journal of Obstetrics and Gynaecology 689 Ierullo et al. average operating time of 73 minutes (range 20–178 minutes).17 We previously described an alternative, simpler, faster technique for undertaking selective laser ablation using preoperative ultrasound identification of the placental common villous district and vascular equator of the placenta by determining the umbilical cord placental insertion sites.18 The aim of this study was to evaluate the use of the placental vascular equator technique for fetoscopic laser ablation in severe TTTS. Methods Between January 2002 and March 2006, fetoscopic laser coagulation was carried out in 77 pregnancies complicated by severe TTTS (Quintero stage III or IV).19 In all cases, firsttrimester ultrasound established monochorionicity by showing a single placental mass and the absence of the lambda sign of the intertwin membrane.20 All pregnancies showed characteristic ultrasound features of TTTS: polyhydramnios (deepest vertical pool of ‡8 cm) and a distended bladder in the recipient, and oligohydramnios (deepest vertical pool of £1 cm) and a collapsed bladder in the donor. The Quintero staging system was used to describe the severity of the TTTS.19 Women were counselled regarding the possible outcomes of the available options, including expectant management, amnioreduction and fetoscopic laser coagulation. Preoperative ultrasound assessment Prior to the procedure, ultrasound was used to visualise the placental site, the donor and recipient umbilical cord placental insertions and to identify the common villous district of the placenta, as previously described.18 In short, the common villous district was estimated to run midway and perpendicular to an imaginary line running between the donor and recipient cord placental insertion sites.18 The anatomical relationship of the cord insertions and common villous district described above are well established.21 In 2005, this anatomical relationship was used to accurately describe placental territories in a placental morphology study after fetoscopic laser ablation.22 The marginal cord insertions seen in the majority of TTTS pregnancies mean that the common villous district is usually eccentrically positioned, with a smaller placental territory for the donor. The placental disc, cord insertions and vascular equator were then marked on the maternal abdomen to help determine the site of fetoscope entry and to shorten operating times. Operative procedure The fetoscope entry site was chosen in order to enter the recipient sac on the opposite side of the uterus to the placenta without injury to the mother or the fetuses. Local anaesthesia (1% lignocaine) was injected from skin to myometrium, 690 and intravenous antibiotic prophylaxis (cefuroxime 750 mg) and intravenous maternal sedation (5–10 mg diazepam as required) were given perioperatively. A rigid 2-mm-diameter 0° fetoscope in a 2.8-mm operating sheath (Olympus Keymed, Southend-on-Sea, UK) was introduced into the recipient sac under continuous ultrasound guidance. A 400-mm-diameter laser fibre (KTP/Nd:YAG Laserscope; Gwent, UK) was passed down the operating channel until the tip was just visible through the fetoscope. When the placenta was positioned anteriorly, a lateral fetoscope insertion in the maternal flank was used, and the maternal abdomen was depressed manually to bring the equatorial region into view. Ultrasound guidance was used to bring the fetoscope tip close to the common villous district previously marked on the maternal abdomen. Once the placenta was visible fetoscopically, the rest of the procedure was conducted under direct vision. Transabdominal ultrasound was used to guide the tip of the fetoscope along the predrawn line on the abdomen, and fetoscopy was used to visualise the vessels directly. The fetoscope was always orientated using a ‘cardinal’ point system: north (donor cord insertion) and south (recipient cord insertion). The fetoscope was then moved along the ultrasonographically determined common villous district (traversing the placenta in an east–west orientation) to visualise any vessels crossing the placental equator. All vessels judged to cross the vascular equator were coagulated using a pulsed laser with an output of 30–60 watts in 3-second bursts. In the vast majority of cases, the vessels seen in the common villous district were not paired by another vessel from the same fetus. Such single, unpaired vessels were always photocoagulated. On rare occasions, paired vessels from the same twin were seen in the common villous district. These were ablated whenever vessels from the co-twin were visible in close proximity in order to ensure that there were no persistent postoperative intertwin vascular connections. At the end of the procedure, amniotic fluid was drained until the amniotic fluid index in the recipient normalised. A 40-ml recipient amniotic fluid sample was always sent for fetal karyotyping. In order to reduce the risks for preterm delivery, tocolytic therapy (glyceryl trinitrate patch 5 mg) was administered for 24 hours. The women were discharged from the hospital from 8 hours postoperatively, and serial follow-up appointments to check the effects of therapy were scheduled for 2 and 8 weeks later. Outcome variables The outcomes measured included the severity of the TTTS at presentation, operative details (gestation, operative time from fetoscope insertion to removal, laser power used and amount of fluid drained), delivery details (gestation and birthweight) and perinatal outcome (spontaneous miscarriage, medical termination, intrauterine death, neonatal death and infant survival). Outcome measures were evaluated on the basis of ª 2007 The Authors Journal compilation ª RCOG 2007 BJOG An International Journal of Obstetrics and Gynaecology Laser ablation of the placental equator in TTTS the number of pregnancies or the number of fetuses or infants, as appropriate. Table 2. Obstetric outcomes with details of survival (%), gestational age range at delivery (%) and birthweight (median and range) Statistical analysis No. of pregnancies (%) Continuous variables were reported as medians (±range). In the analysis of the time to delivery, data were censored at the time of the termination of pregnancy. Results Seventy-seven monochorionic twin pregnancies were diagnosed with severe TTTS and underwent fetoscopic laser ablation during the study period. All cases were diagnosed as either Quintero stage III (n = 68) or stage IV (n = 9). The cord insertion was noted to be marginal in 67 (87%) donors and central in 61 (79%) recipients. The operative details are shown in Table 1. An average of four (range 1–11) vessels were photocoagulated intraoperatively. The delivery details and perinatal outcomes are shown in Tables 2 and 3. The median interval between treatment and delivery in all pregnancies, including miscarriages, was 9 weeks (interquartile range 3– 13 weeks). There was at least one surviving infant in 74% (95% CI: 63–83%) of the pregnancies treated. The overall fetal survival rate was 57% (88/154, 42 donors and 46 recipients). There were five spontaneous miscarriages within 7 days of the procedure (Table 3, ten fetal losses). In a further six pregnancies (seven fetuses), the parents requested medical termination of pregnancy because of the death of one twin (n = 3) or the diagnosis of cerebral haemorrhage (n = 4). In the latter four cases, the diagnosis was made immediately after the procedure because amniodrainage significantly improved ultrasound visualisation. There was no evidence of a recurrence/persistence of TTTS or fetal anaemia evident on ultrasound monitoring in the continuing pregnancies. Repeat fetoscopic laser ablation, amniodrainage or fetal intravascular transfusion was not required prior to delivery in any of the cases. Discussion The aim of fetoscopic laser ablation for treatment of TTTS is to interrupt the abnormal placental vascular communicaTable 1. Operative outcomes with details of gestational age at treatment, operating time from fetoscope entry to exit, amount of laser energy used for the ablation and quantity of amniotic fluid drained at the end of the procedure Survival, n 0 survivors At least one survivor One survivor Two survivors Gestational age at delivery (weeks) ,24 24 to ,28 28 to ,32 32–37 Birthweight (g) Recipient Donor 20 (16–26) 15 (5–25) 2526 (469–9254) 1000 (200–7000) 16 (21) 14 (18) 7 (9) 40 (52) Median (range) 2016 (565–3519) 1539 (436–2752) tions, which are assumed to be the underlying mechanism of the syndrome.23 Although the most recent randomised trial proposes that fetoscopic ablation should be undertaken regardless of the severity of TTTS,5 a systematic review of TTTS treatment suggests that fetoscopic intervention may not be justified in less severe (stages I and II) TTTS cases.16 Furthermore, it is difficult to be certain of the diagnosis of TTTS with stage I (amniotic fluid discordance) and stage II (absent bladder in the presumed donor), as these ultrasound signs may be seen transiently in a normal twin pregnancy. This study provides information on outcome after selective fetoscopic laser ablation for severe (stages III and IV) TTTS. Pregnancy outcome after fetoscopic laser ablation The survival rate of at least one baby per pregnancy for severe TTTS in this study was 74% (95% CI 63–83%). About onethird of pregnancies deliver very prematurely before 28 weeks of gestation (Table 2). Of the 16 pregnancy losses before 24 weeks of gestation, it should be noted that six pregnancies (seven fetuses) were medically terminated either because pre-existing cerebral haemorrhage became evident immediately after amniodrainage at fetoscopic laser treatment or at the parents request after co-twin death (Table 3). There have Table 3. Fetal and perinatal mortalities, expressed as number of fetuses and percentage of 154 fetuses overall n (%) Median (range) Gestational age (weeks) Operating time (minutes) Laser power (joules) Amniotic fluid drained (ml) 20 (26) 57 (74) 26 (34) 31 (40) Termination Miscarriage Intrauterine death Neonatal death ª 2007 The Authors Journal compilation ª RCOG 2007 BJOG An International Journal of Obstetrics and Gynaecology 7 (5) 10 (6) 39 (25) 10 (6) 691 Ierullo et al. been numerous small reports on the success or survival rates after fetoscopic laser ablation.5–7,17,24–26 However, most of these studies have been too small to quote specific survival rates for severe TTTS, and the cases are mixed with regards to whether a selective or nonselective approach was used. Only two previous multicentre studies reported on stage-based (III and IV) survival rates for severe TTTS: Senat et al.5 quoted a 66% (95% CI 48–81%) survival using the nonselective technique in 35 pregnancies. Quintero et al.17 reported a 79% (95% CI 64–91%) survival rate (including terminations) using the selective technique in 74 pregnancies. These rates compare very favourably with the survival rate of 74% from 77 pregnancies in this single-centre study. Equatorial, highly selective and nonselective fetoscopic techniques The equatorial technique described here for performing selective laser ablation made it possible to perform all procedures under local anaesthesia and led to a short median fetoscopy time of 15 minutes (range 5–25 minutes). The shorter fetoscopy times were achieved in cases with a posterior placenta where both cord insertions were marginal resulting in only one or two anastomoses in the vascular equator. Such anastomoses required only 6 to 9 seconds of laser energy and repeat visualisation 1 to 2 minutes later to ensure that recanalisation had not occurred. This should be compared with the use of general anaesthesia and mean operating time of 72 minutes (range 20–178 minutes) from the only previous report of highly selective laser photocoagulation to state the length of the procedures.17 Although it is not possible to relate shorter operating times and the selective technique to improved pregnancy outcomes directly, the avoidance of general anaesthesia and associated complications in a gravid woman are clearly advantageous. The donor cord insertion is marginal in the majority of TTTS cases, thereby locating the placental equator eccentrically with approximately 30–40% of the placental territory belonging to the donor. The survival of 42 donors and 46 recipient twins in the current cohort indicates that significantly increased losses in donor twins are not seen with the equatorial technique. The nonselective technique uses the intertwin dividing membrane as an anatomical landmark, and all vessels traversing the membrane are photocoagulated.4 However, as a consequence of the increased amniotic fluid volume in the recipient sac, the dividing membrane is pushed towards the donor fetus. Using the intertwin membrane as an anatomical landmark may well reduce operating times but increases the likelihood of excessive destruction of the donor placental territory. In 2000, a highly selective coagulation technique was described, where only the vessels involved in intertwin blood transfusion are photocoagulated.17 In the selective technique, a lengthy fetoscopic survey of placental surface vessels is 692 undertaken to identify the vascular communications between the donor and the recipient twin. In a study comparing the two techniques, selective laser photocoagulation appeared to be slightly more effective in the treatment of TTTS when compared with the nonselective technique.17 However, the cases were not comparable as nonselective laser was undertaken in more severe TTTS cases. Furthermore, the differences in survival were only just significant when one-tailed Fisher’s exact test was used but not significant with a twotailed test. Late complications after fetoscopic laser Apart from intrauterine death and miscarriage, late fetal complications after fetoscopic laser treatment have been described.17,26–29 The most common of these are recurrence of TTTS, reversal of TTTS and fetal anaemia after intrauterine death of the co-twin, all as a consequence of persistent or recanalised intertwin vascular connections. The best estimates of the incidence of these complications are provided in a study of 151 cases of TTTS treated by selective fetoscopic laser therapy.30 The study showed a recurrence of TTTS in 14% of cases and fetal anaemia severe enough to require transfusion in 13%.30 The were managed by repeat fetoscopic laser, intrauterine blood transfusion or delivery.30 In the current single-centre cohort, none of the continuing cases showed recurrence of TTTS or fetal anaemia after co-twin death. Although the simpler and faster equatorial technique may not result in improved survival rates, it would be appropriate to speculate that it results in a more effective separation of the fetal circulations, thereby preventing these late complications. Conclusion Fetoscopic laser ablation is a safe and effective form of treatment in the management of severe TTTS with significant advantages over aggressive serial amniodrainage. 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