OBJECTIVE: To assess perinatal outcome in monochorionic twin pregnancies according to different stages of severe mid-trimester twin–twin transfusion syndrome managed by fetoscopic laser coagulation of the placental vascular anastomoses.
METHODS: In a prospective study fetoscopic laser therapy was performed in 200 consecutive pregnancies with severe mid-trimester twin–twin transfusion syndrome at a median gestational age of 20.7 weeks (range 15.9–25.3 weeks). Outcome data were analyzed for the whole group and separately for each stage according to the Quintero staging system.
RESULTS: The overall survival rate was 71.5% (286/400), with survival of both twins in 59.5% (119/200) and survival of at least one of the twins in 83.5% (167/200). The median gestational age at delivery of liveborn neonates was 34.3 weeks (range 23.1–40.4 weeks). There was a significant trend toward reduced survival rates with increasing stage (P=.038). The percentage of pregnancies with survival of both fetuses was 75.9% (22/29) for stage I, 60.5% (49/81) for stage II, 53.8% (43/80) for stage III, and 50% (5/10) for stage IV. At least one of the twins survived in 93.1% (27/29) at stage I, 82.7% (67/81) at stage II, 82.5% (66/80) at stage III, and 70% (7/10) at stage IV. The overall survival rate for donor fetuses was 70.5% (141/200) and for recipient fetuses, 72.5% (145/200).
CONCLUSION: These data show that laser therapy is an effective therapeutic option for all stages of severe twin–twin transfusion syndrome and provide information to counsel patients according to the stage of the syndrome.
LEVEL OF EVIDENCE: II-3
Laser therapy is an effective therapeutic option for all stages of severe twin&#x2013;twin transfusion syndrome.
From the 1Department of Obstetrics and Fetal Medicine, University Medical Center Hamburg-Eppendorf (UKE), Hamburg, Germany; 2Parexel Department of Biometry and Statistics, Westend Hospital, Berlin, Germany; and 3Department of Prenatal Diagnosis and Therapy, Allgemeines Krankenhaus Barmbek, Hamburg, Germany.
Agnes Huber is recipient of a fellowship from the European Commission through its fifth framework program as part of the EuroTwin2Twin project (contract GLC1-CT-2002–01632).
Corresponding author: Kurt Hecher, MD, Department of Obstetrics and Fetal Medicine, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, D-20246 Hamburg, Germany; e-mail: email@example.com.
Monochorionic twin pregnancies represent a high-risk group for adverse pregnancy outcome. Although unequal placental sharing may lead to selective intrauterine growth restriction of one twin, unequal blood flow by placental anastomoses may cause amniotic fluid discordance1 or severe mid-trimester twin–twin transfusion syndrome. If left untreated, perinatal mortality rates reach 90%.2 During the last decade fetoscopic laser coagulation of placental anastomoses has evolved as the best therapeutic option in severe twin–twin transfusion syndrome, with significantly higher survival rates and reduced risks for neurologic abnormalities in surviving children3–6 as compared with serial amniodrainages. The results of the first 200 pregnancies with severe mid-trimester twin–twin transfusion syndrome treated by fetoscopic laser coagulation at our institution have been published before.7 Neurodevelopmental outcome of children after laser treatment at our institution has been reported recently by Graef et al.8
In 1999 Quintero et al9 introduced a staging system of severe twin–twin transfusion syndrome to facilitate comparison of outcome data describing the pathophysiologic cascade in the development of severe twin–twin transfusion syndrome. The aim of this study was to investigate the outcome for the second set of 200 consecutive pregnancies with detailed analysis according to the stage of the syndrome.
MATERIALS AND METHODS
This was a prospective study on 200 consecutive twin pregnancies with severe mid-trimester twin–twin transfusion syndrome treated by fetoscopic laser coagulation between September 1999 and November 2003. All patients were referred from their obstetricians or other fetal medicine centers, and treatment was performed at a single institution. All patients gave written consent after extensive counseling. Ethical committee approval for the fetoscopic laser coagulation was obtained. In each twin, the following investigations were performed before laser treatment: detailed fetal anomaly scan including biometry and echocardiography, amniotic fluid volume (deepest vertical pool), placental location, and Doppler investigation of the umbilical artery and ductus venosus.
All patients fulfilled the study inclusion criteria for severe twin–twin transfusion syndrome based on the criteria proposed by Quintero et al,9 with gestational age less than 26 weeks, ultrasound diagnosis of a single monochorionic placenta, polyhydramnios in the recipient twin's amniotic cavity (deepest vertical pool 8 cm or more), oligohydramnios or anhydramnios in the donor twin's amniotic cavity (deepest vertical pool 2 cm or less, “stuck twin”), signs of polyuria in the recipient (distended bladder) and oliguria in the donor (small or empty bladder). Exclusion criteria were fetal death, ruptured membranes, and leakage of amniotic fluid or if the patient was in labor.
Twenty-nine pregnancies (14.5%) were classified as stage I, with the bladder of the donor twin still visible, but severe oligohydramnios or anhydramnios in the donor twin's sac (stuck twin) and the bladder showing only a small residual filling without dynamic filling and voiding to be observed.
Eighty-one pregnancies (40.5%) were classified as stage II with the bladder of the donor twin not visible. Stage III comprised 80 pregnancies (40%) with severely abnormal Doppler characteristics in one or both twins defined as absent or reversed end-diastolic velocity in the umbilical artery, reversed a-wave in the ductus venosus, or both. In this group there was also one monoamniotic pregnancy without a stuck twin but all the other signs of stage III twin–twin transfusion syndrome. Ten patients (5%) fulfilled the criteria for stage IV with ascites or hydrops of either twin. In all 10 cases the hydrops was present in the recipient twin.
The intervention was performed under local anesthesia by percutaneous insertion of a 2 mm fetoscope (Storz, Tuttlingen, Germany) through a sheath with a working channel for a 0.4 mm Nd:YAG laser fiber (mediLas 4060 fibertom; Daimler Benz Aerospace, München, Germany) into the amniotic sac of the recipient, as described elsewhere.3,10 In pregnancies with a completely anterior placenta, a 30° fetoscope (Storz) has been used since June 2001. It was our aim to coagulate all anastomoses selectively along the vascular equator of the placenta11. At the end of the procedure, amniotic fluid was drained through the sheath after removal of the fetoscope until a deepest vertical pocket of 4–6 cm was obtained.
None of the pregnancies were excluded from analysis once the fetoscope had been introduced into the amniotic cavity, even if laser coagulation was not possible due to poor visibility owing to previous bleeding into the amniotic cavity, which was the case in two pregnancies. In these cases only amniodrainages were performed. Furthermore, six patients (3%) had previous amniodrainages, with five of these with one amniodrainage and one with two amniodrainages before the laser procedure.
Further pregnancy care was managed by the referring centers, and delivery took place at local hospitals. All prenatal data were collected prospectively and data on obstetric and neonatal outcome at least until discharge from hospital were provided by outcome reports from the referring obstetricians and neonatologists.
Dependencies between ordinal or categorical variables were analyzed with the Mantel-Haenszel χ2 test12 to assess a trend in proportions. For overall comparisons of continuous variables across stages the Kruskal-Wallis test was used. In addition, the Jonckheere-Terpstra test for trend was applied.13 Due to the comparatively small sample size for stage IV, this test was applied also to a reduced data set after removal of stage IV pregnancies, but the results did not change substantially. Therefore, the reported P values are derived from the analysis of the total population.
The median gestational age at laser surgery and at delivery of liveborn neonates as well as the median amount of amniotic fluid drained during the procedure and the birth weights for each stage are shown in Table 1. The Kruskal-Wallis test showed a significant overall difference between stages in gestational age at the procedure (P<.001), amount of amniotic fluid drained (P=.005), and interval between procedure and delivery (P=.01).
The overall survival rate was 71.5% (286/400). The percentage of pregnancies with survival of both fetuses was 59.5% with a 95% confidence interval (CI) of 52.4–66.4% (119/200). Survival of only one fetus occurred in 24% (95% CI 18.3–30.5%) (48/200) of pregnancies, thus resulting in a survival rate for at least one fetus of 83.5% (95% CI 77.6–88.4%) (167/200). The survival rate for recipient fetuses was 72.5% (95% CI 65.8–78.6%) (145/200) and 70.5% (95% CI 63.7–76.7) (141/200) for donor fetuses.
Seven (3.5%) patients had a miscarriage after the laser procedure. Four (2%) patients decided to terminate the pregnancy after the laser procedure due to rupture of membranes and development of ventriculomegaly, in two cases respectively. Intrauterine fetal death of one twin occurred in 45 (22.5%) cases (23 recipient twins and 22 donor twins). Intrauterine death of both twins occurred in 14 (7%) pregnancies. There were 19 out of 305 (6%) liveborn babies where neonatal death occurred. In 6 twin pairs deaths of both neonates occurred and there were two cases with previous intrauterine death of the co-twin. The detailed survival rates according to the Quintero stages are shown in Table 2. There was a significant overall trend toward reduced survival rates with increasing stage (Mantel-Haenszel χ2 test: P = .038). There were no serious maternal complications during or after fetoscopy, ie, no need for blood transfusions, laparotomy, or admittance to an intensive care unit.
This study of a large population of pregnancies with severe twin–twin transfusion syndrome with detailed stage-dependent analysis of outcome shows that laser therapy is an effective therapeutic option for all stages of severe mid-trimester twin–twin transfusion syndrome. With advancing stage a gradual decline in survival rates could be observed, without a difference in survival rates between recipient and donor twins. More severe stages tended to present at an earlier gestational age, indicating that stage progression does not necessarily represent a time cascade in the pathophysiology of the development of twin–twin transfusion syndrome. Alternatively, the process may have started earlier in gestation or they may have progressed faster than other cases.
Compared with our first series of 200 pregnancies treated in our department,7 a further increase in survival rates could be observed. Overall survival rates increased from 65% to 71.5%, survival of both fetuses from 50% to 59.5%, and survival of at least one fetus from 80.5% to 83.5%. In our previous series, survival rates for recipient fetuses were 71.5% and for donor fetuses 59%, and have now become almost the same for both (72.5% and 70.5%, respectively). Thus, the increase in overall survival may be explained by the increase in survival of donor fetuses due to the strictly selective coagulation of placental anastomoses along the vascular equator. Furthermore, our recently published study on neurologic follow-up after laser treatment showed 87% of children with normal neurodevelopmental outcome, 7% with minor, and only 6% of survivors with major neurologic abnormalities.8
In a recent study, Quintero et al14 examined the minimal individual placental territory that was associated with survival of both fetuses after selective laser coagulation for twin–twin transfusion syndrome. Their results showed that survival can occur with as little as 14% of placental mass for donor and 20% for recipient twins. Lesser individual placental territories after laser coagulation may be responsible for early and late intrauterine demise after the procedure.
With a median gestational age of 20.7 weeks at the time of the intervention, there was no difference from previous studies. However, more severe stages presented and were treated at a significantly earlier gestational age without a significant difference in median gestational age at delivery, thus indicating that preoperative staging did not influence the further course and obstetric management of the pregnancy, whereas the decline in survival may be attributed to higher fetal loss rates with advancing stage.
Quintero et al15 reported stage-dependent survival rates after laser coagulation at the same median gestational age in a series of 95 pregnancies. They described an overall survival rate of 64.2%, with stage-dependent survival rates of 76.2 % (stage I), 67.1% (stage II), 51.8 (stage III), and 63.6% (stage IV). In contrast to their conclusions, we suggest laser coagulation for stage I as well, owing to higher survival rates in our population. Furthermore, Duncombe et al16 reported on the outcome of 22 cases with stage I treated by amnioreduction with a perinatal survival rate of 77.3% and with at least one surviving twin in 86.4%. However, the best therapeutic option for stage I at a more advanced gestational age may still be seen controversial, with amnioreduction being an alternative, if laser coagulation is not available.
Doppler studies of the fetal circulation allow assessment of cardiac function and severely abnormal venous flow velocity waveforms are indicative of congestive heart failure. In a study by Zikulnig et al10 on prognostic factors in severe twin–twin transfusion syndrome, both absent or reversed a-wave in the ductus venosus and absent or reversed end-diastolic velocities in the umbilical artery of the recipient had a significant negative influence on the survival rate. These pregnancies would have been classified as stage III, and the results are in accordance with our stage-dependent analysis. The decline of drained amniotic fluid volume with advancing stage may on the one hand be due to the earlier gestational age at presentation and on the other hand be a consequence of a decline in urine production of the severely hemodynamically compromised recipient twin. This is in accordance with the clinical observation that in hydropic recipient twins (stage IV) bladder filling is not as pronounced as in less severe stages.
It is noteworthy that even for stage IV, where hydrops was present in all recipient twins, in 70% there was at least one survivor and in 50% both twins survived, resulting in an overall survival rate of 60%. Therefore, it does not seem to be justified to sacrifice the hydropic recipient twin by selective feticide for the sake of its co-twin as a first-line therapy. This procedure, which by definition can never achieve an overall survival rate of more than 50%, should be reserved for selected cases with failure of laser or preoperative sonographic signs of brain damage in one twin. In their series on selective feticide in 46 complicated monochorionic twin pregnancies, Robyr et al17 reported a survival rate of 72%, corresponding to an overall survival rate of 36%, after selective feticide of the co-twin. Poor outcome of the procedure appeared to be associated with performance of the procedure before 18 weeks. Deprest et al (Deprest J, Lewi L, Gratacos E, Ortibus E, Devlieger R, Carreras E. Selective feticide in monochorionic twins [abstract]. Ultrasound Obstet Gynecol 2005;26:322) reported a survival rate of 83%, corresponding to an overall survival rate of 41.5%, after selective feticide of the co-twin, with 7% of survivors not developing normally at more than 1 year of age, the majority after preterm delivery and preterm premature rupture of membranes.
A potential limitation of this study may be the fact that laser therapy was performed at one single institution, which theoretically could reduce generalizability of the data. However, the criteria and technique for fetoscopic laser therapy are the same for all experienced centers; therefore, the results may be generally applicable for other institutions.
In summary, this study shows that laser therapy is an effective therapeutic option for all stages of severe mid-trimester twin–twin transfusion syndrome. On the basis of these stage-related outcome data, patients may be counseled in more detail and according to the stage of the syndrome.
1. Huber A, Diehl W, Zikulnig L, Bregenzer T, Hackelöer BJ, Hecher K. Perinatal outcome in monochorionic twin pregnancies complicated by amniotic fluid discordance without severe twin-twin transfusion syndrome. Ultrasound Obstet Gynecol 2006;27:48–52.
2. De Lia JE. Surgery of the placenta and umbilical cord. Clin Obstet Gynecol 1996;39:607–25.
3. Hecher K, Plath H, Bregenzer T, Hansmann M, Hackelöer BJ. Endoscopic laser surgery versus serial amniocenteses in the treatment of severe twin-twin transfusion syndrome. Am J Obstet Gynecol 1999;180:717–24.
4. Banek, CS, Hecher K, Hackelöer BJ, Bartmann P. Long-term neurodevelopmental outcome after intrauterine laser treatment for severe twin-twin transfusion syndrome. Am J Obstet Gynecol 2003, 188:876–80.
5. Senat MV, Deprest J, Boulvain M, Paupe A, Winer N, Ville Y. Endoscopic laser surgery versus serial amnioreduction for severe twin-to-twin transfusion syndrome. N Engl J Med 2004;351:136–44.
6. Fox C, Kilby MD, Khan KS. Contemporary treatments for twin-twin transfusion syndrome. Obstet Gynecol 2005;105:1469–77.
7. Hecher K, Diehl W, Zikulnig L, Vetter M, Hackelöer BJ. Endoscopic laser coagulation of placental anastomoses in 200 pregnancies with severe mid-trimester twin-to-twin transfusion syndrome. Eur J Obstet Gynecol Reprod Biol 2000;92:135–9.
8. Graef C, Ellenrieder B, Hecher K, Hackelöer BJ, Huber A, Bartmann P. Long-term neurodevelopmental outcome of 167 children after intrauterine laser treatment for severe twin-twin transfusion syndrome. Am J Obstet Gynecol 2006;194:303–8.
9. Quintero RA, Morales WJ, Allen MH, Bornick PW, Johnson PK, Kruger M. Staging of twin-twin transfusion syndrome. J Perinatol 1999;19:550–5.
10. Zikulnig L, Hecher K, Bregenzer T, Baez E, Hackelöer BJ. Prognostic factors in severe twin-twin transfusion syndrome treated by endoscopic laser surgery. Ultrasound Obstet Gynecol 1999;14:380–7.
11. Huber A, Hecher K. How can we diagnose and manage twin-twin transfusion syndrome? Best Pract Res Clin Obstet Gynaecol 2004;18:543–56.
12. Mantel N, Haenszel W. Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst 1959;22:719–48.
13. Pirie W. Jonckheere tests for ordered alternatives. In: Kotz S and Johnson NL, editors. Encyclopedia of statistical sciences. Volume 4. New York (NY): John Wiley & Sons, Inc.; 1982. p. 315–18.
14. Quintero RA, Martinez JM, López J, Bermùdez C, Becerra C, Morales W, et al. Individual placental territories after selective laser photocoagulation of communicating vessels in twin-twin transfusion syndrome. Am J Obstet Gynecol 2005;192:1112–8.
15. Quintero RA, Dickinson JE, Morales WJ, Bornick PW, Bermudez C, Cincotta R, et al. Stage-based treatment of twin-twin transfusion syndrome. Am J Obstet Gynecol 2003;188:1333–40.
16. Duncombe GJ, Dickinson JE, Evans SF. Perinatal characteristics and outcomes of pregnancies complicated by twin-twin transfusion syndrome. Obstet Gynecol 2003;101:1190–6.
17. Robyr R, Yamamoto M, Ville Y. Selective feticide in complicated monochorionic twin pregnancies using ultrasound-guided bipolar cord coagulation. BJOG 2005,112: 1344–8.