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ORIGINAL RESEARCH |
From the Centre for Fetal Care, Department of Maternal and Fetal Medicine, Imperial College of Science, Technology and Medicine, Queen Charlotte’s & Chelsea Hospital, London, United Kingdom.
Address reprint requests to: M. J. O. Taylor, MRCOG, Imperial College of Science, Technology and Medicine, Queen Charlotte’s & Chelsea Hospital, Department of Maternal and Fetal Medicine, Du Cane Road, London W12 0HS, United Kingdom; E-mail: myles.taylor{at}ic.ac.uk.
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ABSTRACT |
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METHODS: Prospective observational study in a tertiary referral fetal medicine center of 52 consecutive cases of twin-twin transfusion syndrome. Each pregnancy was assessed longitudinally for a variety of prognostic factors including fetal biometry, amniotic fluid volume, arterial and venous Doppler sonogram abnormalities, and the presence of hydrops. Data were used to determine stage at diagnosis and first treatment, and worst stage throughout pregnancy. Perinatal outcome was assessed by stage. Management comprised serial amnioreduction, septostomy, selective reduction, or delivery, alone or in combination.
RESULTS: Median gestation at presentation and first treatment were both 21 weeks (range 14–34 and 15–34), and at delivery it was 29 weeks (range 16–40). Sixty-three percent of pregnancies (33 of 52) were at least stage III at presentation. Forty-five percent of pregnancies (22 of 49) progressed to a more advanced stage. Overall survival was 47% (47 of 100), with no difference between donor and recipient fetuses (40% [20 of 50] versus 54% [27 of 50] [
2 P < .5]). Survival rates were 58% (15 of 26), 60% (six of ten), 42% (20 of 48), 43% (six of 14), and 0% (none of two) for stages I–V, respectively, with no significant influence of stage at presentation on survival. Survival was poorer where stage increased, versus decreased (27% [12 of 44] versus 94% [17 of 18] 2 P < .001). Kaplan-Meier survival curves indicated that staging at presentation identified pregnancies at greater risk of earlier rather than later gestational perinatal loss.
CONCLUSION: The Quintero staging system did not distinguish good from bad outcome at presentation, and thus should be used with caution in guiding initial management of twin-twin transfusion syndrome. However, prognosis was influenced by a change in stage, and pregnancies progressing to higher stage disease were at increased risk of earlier perinatal loss. Staging may thus be more useful in monitoring disease progression.
Twin-twin transfusion syndrome complicates 15% of monochorionic pregnancies as a result of unbalanced blood flow through vascular communications on the chorionic plate.1 Untreated, the prognosis is poor, with an overall perinatal mortality of 80%.2
The diagnosis of twin-twin transfusion syndrome is largely based on sonographic findings of disparate liquor volumes in the two amniotic sacs; additional findings may include a stuck donor with nonvisualization of the bladder,1 arterial and/or venous Doppler abnormalities,3,4 hydrops,5 and an absence of arterioarterial anastomoses.6 Treatment options are serial amnioreduction,7–9 endoscopic laser ablation of intertwin anastomoses,10,11 septostomy,12,13 and selective feticide14 by bipolar cord occlusion. Amnioreduction and septostomy are simple procedures, which primarily control amniotic fluid volume but may also ameliorate other features of the disease.15 In contrast, laser ablation and selective feticide are technically difficult procedures, which aim primarily to interrupt intertwin transfusion,16,17 A recent meta-analysis has shown that the overall survival rates for twin-twin transfusion syndrome cases presenting at less than 28 weeks treated by laser or amnioreduction are similar, at 59% and 58%, respectively.2 Single survival rates of 80–90% have been reported for both laser and selective feticide,16,18,19 although laser in two recent series has the advantage that both infants may survive 30–50% of the time.18,19 The choice thus appears to be between simple, safer, less effective therapies and technically challenging, more effective procedures with substantial complication rates.16,17
As with many medical disorders, the concept of staging a disease has been developed not only to assist prognostication, but also to help select optimal treatment options and to compare outcome results between centers. Quintero et al20 considered the sequence of events with progressive disease and thus devised a staging system for twin-twin transfusion syndrome. Their staging was both intuitive and in keeping with our own observations that twin-twin transfusion syndrome progresses from liquor discordancy to nonvisualization of the donor bladder (oliguria or anuria) with either the donor or recipient later developing abnormal venous or arterial Doppler waveforms, which can subsequently progress to hydrops and single or double intrauterine death. Quintero et al retrospectively validated their staging system, largely on patients who were treated by laser ablation, which undermines their validation because of laser’s ability to reverse the disease phenotype, on the one hand, and its known incidence of procedure-related loss on the other. Furthermore, it is unclear whether validation was determined at presentation or at first treatment.
Ideally, staging should be validated on untreated patients where the natural history of the disease can be studied. Otherwise, treatments, if effective, will inevitably distort the findings by improving outcomes of those with worse disease—the treatment paradox. As with cancer, however, there are ethical constraints against pursuing such studies. In contrast to laser, palliative treatments of septostomy and amnioreduction, though effective, may not necessarily mask the natural history of twin-twin transfusion syndrome. Thus, although Quintero et al showed significant differences in the survival of zero, one, or two fetuses between stages, no differences in overall fetal survival were seen by stage in their laser patients. In contrast, overall survival was significantly improved in those with early stage disease treated by amnioreduction, but this was in only nine patients. To validate the Quintero staging system further, analysis of outcomes in patients treated by palliative techniques is required to minimize the effect of the treatment paradox. Therefore, we attempted to validate Quintero staging system in a prospectively monitored cohort of twin-twin transfusion syndrome patients, primarily treated by conservative therapy, amnioreduction, and septostomy, but in extremis also by selective feticide. Individual outcomes based on initial presentation, first treatment, and worst stage were compared.
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MATERIALS AND METHODS |
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The deepest vertical pool was measured in each sac and a total amniotic fluid index (AFI) derived as for singletons.23 The diagnosis of twin-twin transfusion syndrome was based on ultrasound criteria of discordant amniotic fluid volume—that is, polyhydramnios in one and oligohydramnios in the other defined by deepest vertical pools of more than 8 cm and less than 2 cm, respectively,24,25 in monochorionic diamniotic twins. In addition, characteristics of the donor (smaller size, reduced liquor volume, reduced bladder volume) and recipient fetuses (increased size, polyhydramnios, chronically full bladder, and cardiomegaly) were sought to distinguish twin-twin transfusion syndrome from monochorionic diamniotic twins complicated by discordant growth restriction.
Gestational age was based on the date of the last menstrual period, if certain, or otherwise ultrasound in the first trimester. Each case was assessed for the following: biometry, amniotic fluid volumes, arterial and venous Dopplers, and the presence of hydrops, defined as the abnormal collection of fluid in any of the abdominal, pleural, and pericardial body cavities or within the subcutaneous tissue space, in either the donor or the recipient fetus.
We obtained umbilical artery (UA) Doppler recordings from each twin, taking care to ensure that these were not inadvertently taken from the cotwin by following each cord to its insertion using color flow imaging. In the recipient, venous Doppler insonation of the umbilical vein (UV) and ductus venosus was undertaken.4 We deemed abnormal any regular pulsatility in the UV synchronous with the cardiac cycle or absent or reversed flow in the ductus venosus during atrial contraction.
We confirmed nonvisualization of the bladder in the donor over time by persistent lack of separation of the vitelline arteries on color Doppler. Arterioarterial anastomoses were identified using color Doppler energy recordings as previously described.26 All patients were examined vaginally to exclude spontaneous rupture of membranes or cervical change indicative of preterm labor.
All measurements were taken at the time of presentation with twin-twin transfusion syndrome and at subsequent visits. Each case was staged according to the presence of prognostic factors20 (Table 1
).
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Management comprised serial amnioreduction (n = 21), septostomy (n = 3), or selective reduction alone (n = 6). Combined therapies of amnioreduction and septostomy (n = 2), amnioreduction and selective termination (n = 4), and amnioreduction and septostomy and selective termination (n = 2) were also used. Selective reduction was performed using bipolar diathermy16 in all but one case, where interstitial laser was used at 15 weeks. In four cases, delivery was expedited shortly after presentation, whereas eight cases were managed conservatively. Two cases underwent termination of the entire pregnancy.
Fetal loss was defined as any fetus that did not survive beyond the neonatal period (7 days). Parametric tests of analysis of variance and the Student unpaired t test, and nonparametric 2 or the Fisher exact test were used when appropriate, with a P value of less than .05 considered significant. Kaplan-Meier survival curves were used to assess the influence of stage on outcome, and comparisons made using the Peto log-rank test. The two cases of termination of both fetuses were excluded from the survival analysis. Outcomes from some of these patients have been reported elsewhere.26,29
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RESULTS |
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shows the incidence and median gestation of each stage at presentation and first treatment, and worst stage. Sixty-three percent of pregnancies (33 of 52) were at least stage III at presentation. Overall, median gestational ages at presentation and first treatment were both 21 weeks (range 14–34 and 15–34, respectively). There was no significant effect of stage on gestational age at presentation, or at first treatment or at the worst stage (analysis of variance Ps = .09, .24, and .8, and Fs = 2.12, 1.44, and 0.46, respectively). Median gestation at delivery was 29 weeks (range 16–40).
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). Compared with cases with stage I disease at presentation, progression was particularly marked in those with stage IV, where 86% (six of seven) versus 31% (four of 13) of cases progressed to more advanced disease (one-sided Fisher exact test P = .03).
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2 P = .54). Survival rates were 58% (15 of 26), 60% (six of ten), 42% (20 of 48), 43% (six of 14), and 0% (none of two) for stages I–V, respectively (Figure 2), with no survival difference seen either in overall survival (2 x K 2 P = .37) or in terms of at least one fetus surviving according to stage (2 x K 2 P = .48). Survival was poorer in pregnancies where disease increased in stage than in those where stage decreased (27% [12 of 44] versus 94% [17 of 18] [2 P < .001]) (Figure 2). Thus, all fetuses (four of four) survived with a decrease of two in stage, compared with only 23% (seven of 26) when stage increased by two (Fisher exact P = .01). A three-way comparison of survival (stage increased versus stage unchanged versus stage decreased [27% (12 of 44) versus 50% (18 of 36) versus 94% (17/18)] [2 x K 2 P < .001]) also showed improved outcome with decrease in stage.
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2 P = .07) (Figure 2
).
Kaplan-Meier survival curves (Figure 3) indicated that staging at presentation did not influence hazard ratios and thus did not obviously distinguish good from bad outcomes (2 for equivalence of death rates = 2.68, P = .6). However, grouping stage I with II, and III–V together, permitted some discrimination in outcomes, with lower stage disease showing a reduced hazard ratio (0.53; confidence interval 0.3, 0.9) (2 for equivalence of death rates = 4.9, P = .03) relative to more advanced disease. Thus, at 21 weeks, 94% of fetuses (34 of 36) still survived who had stages I and II at presentation, versus only 63%(40 of 64) with higher stages (2 P < .001). After 29 weeks this survival advantage was no longer apparent (58% [21 of 36] versus 41% [26 of 64], 2 P = .95).
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DISCUSSION |
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There are two potential explanations for our negative findings at presentation. First, the choice of antenatal factors used to derive the staging system may be inappropriate—either individually or collectively nonpredictive. Second, our results may reflect effective treatment rendering apparently severe cases more benign—the so-called treatment paradox.
Few antenatal factors have been shown independently to be predictive of outcome. Mari et al30 reported that the presence of hydrops in the recipient and absent end diastolic flow in the UA Doppler waveform of the donor were associated with a poor outcome. In another series, in addition to hydrops, the use of amnioreduction was also predictive of poor outcome.5 In contrast, reaccumulation of urine in the bladder of the "stuck twin" has been suggested to be predictive of a better chance of survival.31 Our own group tested the ability of ten antenatal factors to predict outcome in twin-twin transfusion syndrome and identified three that independently predicted poor outcome: absent end diastolic flow in the donor UA Doppler, abnormal venous Dopplers in the recipient, and the absence of an arterioarterial anastomosis on chorionic plate Doppler studies.32
In the staging system examined in this study, the outcomes of stage I were indistinguishable from those of stage II. This suggests that the oligohydramnios-polyhydramnios sequence (stage I) or the absence of a visible bladder in the donor (stage II) does not per se provide prognostic information. They may do so later, if these features persist or worsen, as suggested by our observation that only the worst stage reached in a particular pregnancy was predictive of outcome. In contrast, critically abnormal arterial or venous Dopplers (stage III) have been evaluated and shown to be predictive of poor outcome, as has the presence of hydrops (stage IV). This may explain why some discrimination in outcome is apparent if stages I and II are combined and compared with stages III and IV (Figure 3).
Amnioreduction or septostomy is a largely symptomatic or palliative treatment, providing the rationale in the current study for validating the staging system on this treatment group. However, there is evidence that both amnioreduction and septostomy may ameliorate fetal condition in twin-twin transfusion syndrome and alter the underlying pathophysiology. Several groups have reported restoration and maintenance of normal amniotic fluid volumes and/or reduction of hydrops after amnioreduction,9,33,34 whereas our own group has reported increased uterine artery blood flow immediately after amnioreduction, which may benefit fetal condition.35 Thus, studies of amnioreduction or septostomy results may also be limited by the same treatment paradox that affects outcome studies following laser therapy. Selective feticide, used alone in six cases in our series, was not felt to influence overall outcomes, as this technique was only used in extremis when it was judged that one or even both fetuses would otherwise have died.
A further limitation of this study is sample size. Twin-twin transfusion syndrome is a rare disease, with very few series having been published with more than 50 patients from a single center. Our data have the unique advantage that stage was determined at 2-week intervals throughout pregnancy.
Our own group has previously tested the use of a combined antenatal score, derived from ten antenatal factors,32 and found an association with poor outcome, albeit in a series of only 23 patients. When seven of ten risk factors were present, the probability of at least one infant surviving was only 32%. In contrast, if no risk factor was present, the probability of at least one infant surviving was 95% (P = .03). Each of these factors is assessable at the time of diagnosis and therefore, in contrast to the staging system under review, may prove more useful both in counseling parents and in selecting initial management. This requires confirmation in larger series.
When survival was examined according to change in stage (Figure 2), a marked decrease in survival was seen in those whose staging increased versus those in whom staging decreased, suggesting that staging is better suited for monitoring twin-twin transfusion syndrome pregnancies than for prognosticating at the time of diagnosis. Our observation that worst stage ever reached was a good predictor of outcome (Figure 2) supports this notion. However, worst stage is determined in retrospect and is therefore not available to guide patient management, whereas changes in stage can be readily assessed throughout pregnancy.
Although overall survival did not differ according to stage at presentation, Kaplan-Meier survival curves (Figure 3) indicated that pregnancies presenting with higher stage disease were at increased risk of fetal demise at an earlier gestation relative to those with lower stage disease. However, it is not clear how best to benefit from this observation, as Figure 3 shows that any survival advantage in lower stage disease is lost by the third trimester, and elective delivery before this would expose the fetuses to the complications of prematurity.
The results of this study suggest that caution should be used in deciding management of twin-twin transfusion syndrome based upon this staging system, but support it having a role in monitoring disease.
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Footnotes |
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Received January 16, 2002. Received in revised form May 7, 2002. Accepted June 6, 2002.
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REFERENCES |
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2. Fisk NM, Taylor MJO. The fetus(es) with twin twin transfusion syndrome. In: Harrison M, Evans M, Adzick S, Holzgreve W, eds. The unborn patient: The art and science of fetal therapy. Philadelphia: W. B. Saunders Co., 2000:341–55.
3. Hecher K, Ville Y, Nicolaides KH. Fetal arterial Doppler studies in twin-twin transfusion syndrome. J Ultrasound Med 1995;14:101–8.[Abstract]
4. Hecher K, Ville Y, Snijders R, Nicolaides K. Doppler studies of the fetal circulation in twin-twin transfusion syndrome. Ultrasound Obstet Gynecol 1995;5:318–24.[Medline]
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6. Denbow M, Cox P, Talbert D, Fisk N. Colour Doppler energy insonation of placental vasculature in monochorionic twins: Absent arterio-arterial anastomoses in association with twin-twin transfusion syndrome. Br J Obstet Gynaecol 1998;105:760–5.[Medline]
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10. De Lia JE, Cruikshank DP, Keye WR Jr. Fetoscopic neodymium: YAG laser occlusion of placental vessels in severe twin-twin transfusion syndrome. Obstet Gynecol 1990;75:1046–53.
11. Ville Y, Hyett J, Hecher K, Nicolaides K. Preliminary experience with endoscopic laser surgery for severe twin-twin transfusion syndrome. N Engl J Med 1995;332:224–7.
12. Saade GR, Belfort MA, Berry DL, Bui TH, Montgomery LD, Johnson A, et al. Amniotic septostomy for the treatment of twin oligohydramnios-polyhydramnios sequence. Fetal Diagn Ther 1998;13:86–93.[Medline]
13. Hubinont C, Bernard P, Mwebesa W, Magritte J, Donnez J. Nd:YAG laser and needle disruption of the interfetal septum: A possible therapy in severe twin-to-twin transfusion syndrome. J Gynecol Surg 1996;12:183–9.
14. Deprest JA, Audibert F, Van Schoubroeck D, Hecher K, Mahieu-Caputo D. Bipolar coagulation of the umbilical cord in complicated monochorionic twin pregnancy. Am J Obstet Gynecol 2000;182:340–5.[Medline]
15. Umur A, Van Gemert MJ, Ross MG. Fetal urine and amniotic fluid in monochorionic twins with twin-twin transfusion syndrome: Simulations of therapy. Am J Obstet Gynecol 2001;185:996–1003.[Medline]
16. Taylor MJO, Shalev E, Tanawattanacharoen S, Jolly M, Kumar S, Weiner E, et al. Ultrasound guided umbilical cord occlusion using bipolar diathermy for stage III/IV twin-twin transfusion. Prenat Diagn 2002;22:70–6.[Medline]
17. Ville Y, Hecher K, Gagnon A, Sebire N, Hyett J, Nicolaides K. Endoscopic laser coagulation in the management of severe twin-to-twin transfusion syndrome. Br J Obstet Gynaecol 1998;105:446–53.[Medline]
18. Quintero RA, Comas C, Bornick PW, Allen MH, Kruger M. Selective versus non-selective laser photocoagulation of placental vessels in twin-to-twin transfusion syndrome. Ultrasound Obstet Gynecol 2000;16:230–6.[Medline]
19. Hecher K, Diehl W, Zikulnig L, Vetter M, Hackeloer 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.[Medline]
20. Quintero RA, Morales WJ, Allen MH, Bornick PW, Johnson PK, Kruger M. Staging of twin-twin transfusion syndrome. J Perinatol 1999;19:550–5.[Medline]
21. Fisk N, Bennett P. Prenatal determination of chorionicity and zygosity. In: Ward H, Whittle M, eds. Proceedings of the RCOG Study Group on Multiple Pregnancy. London: RCOG Press, 1995:56–67.
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23. Phelan JP, Ahn MO, Smith CV, Rutherford SE, Anderson E. Amniotic fluid index measurements during pregnancy. J Reprod Med 1987;32:601–4.[Medline]
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25. Wittmann BK, Baldwin VJ, Nichol B. Antenatal diagnosis of twin transfusion syndrome by ultrasound. Obstet Gynecol 1981;58:123–7.
26. Taylor MJ, Denbow ML, Tanawattanacharoen S, Gannon C, Cox PM, Fisk NM. Doppler detection of arterio-arterial anastomoses in monochorionic twins: Feasibility and clinical application. Hum Reprod 2000;15:1632–6.
27. Twin-twin transfusion syndrome: A multicenter randomized trial for the evaluation of septostomy versus serial amnioreduction for therapy. Available at: http://www.med.unc.edu/tts/tts. Accessed 2002 Sep 16.
28. Denbow M, Fogliani R, Kyle P, Letsky E, Nicolini U, Fisk N. Haematological indices at fetal blood sampling in monochorionic pregnancies complicated by feto-fetal transfusion syndrome. Prenat Diagn 1998;18:941–6.[Medline]
29. Taylor MJ, Denbow ML, Duncan KR, Overton TG, Fisk NM. Antenatal factors at diagnosis that predict outcome in twin-twin transfusion syndrome. Am J Obstet Gynecol 2000;183:1023–8.[Medline]
30. Mari G, Detti L, Oz U, Abuhamad AZ. Long-term outcome in twin-twin transfusion syndrome treated with serial aggressive amnioreduction. Am J Obstet Gynecol 2000; 183:211–7.[Medline]
31. Kilby MD, Howe DT, McHugo JM, Whittle MJ. Bladder visualisation as a prognostic sign in oligohydramnios-polyhydramnios sequence in twin pregnancies treated using therapeutic amniocentesis. Br J Obstet Gynaecol 1997; 104:939–42.[Medline]
32. Taylor MJO, Denbow ML, Duncan KR, Overton TG, Fisk NM. Antenatal factors at diagnosis predictive of survival in severe twin-twin transfusion syndrome. Am J Obstet Gynecol 2000;183:1023–8.
33. Wax JR, Blakemore KJ, Blohm P, Callan NA. Stuck twin with cotwin nonimmune hydrops: Successful treatment by amniocentesis. Fetal Diagn Ther 1991;6:126–31.[Medline]
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35. Bower SJ, Flack NJ, Sepulveda W, Talbert DG, Fisk NM. Uterine artery blood flow response to correction of amniotic fluid volume. Am J Obstet Gynecol 1995;173:502–7.[Medline]
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