Brown University

Fetal Medicine @ Brown
WARREN ALPERT MEDICAL SCHOOL OF BROWN UNIVERSITY

The Warren Alpert Medical School of Brown University

 CONTEMPORARY EVALUATION AND MANAGEMENT OF TWIN-TWIN TRANSFUSION SYNDROME*

Stephen R. Carr and Michael P. Plevyak
Division of Maternal-Fetal Medicine and Program in Fetal Medicine

Brown Medical School and Women & Infants' Hospital of Rhode Island

*Reproduced with permission from Medicine & Health/Rhode Island 2001;84:165-168.
The May 2001 issue of this journal was published in conjuction with the 2nd Annual Frank G. DeLuca Lectureship in Pediatric Surgical Sciences, entitled "The Smallest Patient: Foundations in Fetal Medicine," organized by the Brown Medical School Program in Fetal Medicine


INTRODUCTION


Twinning rates vary by twin type and location throughout the world. The rate of monozygotic twinning is quite constant worldwide at 3.5/1000 deliveries while dizygotic twinning rates range from 49/1000 deliveries in Nigerian populations to 1.3/1000 deliveries in Japanese populations. Thirty per cent of monozygotic twins result from division of the embryo within the first 72 hours after fertilization and result in monochorionic-diamniotic twins. These are the twins that are at risk for twin-twin transfusion syndrome. Twin pregnancies evidence greater morbidity and mortality than do singleton pregnancies, and among twin pregnancies monozygotic twins have greater morbidity and mortality than do dizygotic twins. The morbidities seen more commonly in monochorionic twins include structural defects and twin-twin transfusion. Twin-twin transfusion syndrome (TTTS) is the consequence of unbalanced blood flow from one twin (the donor) to the other (the recipient) across transplacental vascular communications and results in the polyhydramnios/ oligo- hydramnios sequence and can include growth discordance. These vascular communications (of which there are four types) are present in nearly 100% of monochorionic twins but occur only rarely in dichorionic twins.[1, 2] The diagnosis of TTTS has in the past been based on neonatal findings, but these findings are unreliable for the prenatal detection of the syndrome. Current strategies use ultrasound to determine both the presence and severity of prenatally diagnosed TTTS. Table 1 is a list of the salient points in ultrasound diagnosis of TTTS:

 A. Monochorionic twin gestation
1. Twins of same gender
2. Thin inter-twin membrane
3. Single placenta


B. Discordance in amniotic fluid volume
1. "Donor" twin with decreased fluid (deepest vertical pocket < 2.0 cm is consistent with severe TTTS).
2. "Recipient" twin with increased amniotic fluid volume (deepest vertical pocket > 8.0 cm is consistent with severe TTTS).


C. Other ultrasound findings
1. Appearance of a "stuck" twin that does not change intrauterine position regardless of maternal position.
2. Small or non-visualized bladder in the "donor" twin
3. Large bladder in the recipient twin
4. Abnormal Doppler findings
a. pulsatile umbilical venous blood flow
b. absent or reversed end-diastolic umbilical arterial blood flow
c. tricuspid valve regurgitation.
5. Hydrops: ascites, pleural or epicardial effusions

 Table 1. Ultrasound diagnosis of twin-twin transfusion syndrome (TTTS)

MANAGEMENT OF TTTS


Once diagnosed, untreated TTTS results in morbidity and mortality that exceeds 70%.[3] Despite enthusiasm for different modalities, treatment of TTTS is associated with survival rates of only 60-70%. Even more troubling is the increased incidence of cerebral palsy and other cerebral impairment (from 20-40%) in the surviving co-twin when one of a set of monochorionic twins dies in utero.[4, 5] Several treatment modalities have been used to treat TTTS. Those receiving the most attention include serial amnioreduction, septostomy, and fetoscopic laser ablation of chorioangiopagus vessels (FLOC).

AMNIOREDUCTION


Amnioreduction is the removal of large quantities of amniotic fluid from the polyhydramniotic sac of the recipient twin. This is accomplished using an 18 or 20 gauge needle under ultrasound guidance and is performed from one to several times. Although amnioreduction does not address the postulated cause of TTTS, it is postulated to result in decreased pressure on the transplacental vascular anastamoses, which increases placental compliance, thus reducing the preload and afterload in the hearts of both twins.[6] The reduction in intrauterine volume also appears to decrease the incidence of preterm labor, a major contributor to the morbidity of TTTS. Proponents of amnioreduction point to it's simplicity and success rates; one recent trial of aggressive amnioreduction reported 57% survival of both twins at 24 months of age and 70% survival at 24 months of age of at least one twin.[7] Preterm premature rupture of membranes complicates 8% of pregnancies treated with serial amnioreduction.[8]

SEPTOSTOMY


Septostomy (deliberate creation of a defect in the membrane separating the two twins) has been proposed as a method to equalize the pressures in the twins' amniotic sacs. In this technique a 20 or 22 gauge needle is introduced to the uterine cavity using ultrasound guidance in such a way as to deliberately breach the amniotic membrane overlying the smaller oligohydramniotic sac. A recent study of 12 patients with severe TTTS treated with intentional septostomy yielded 75% survival of both twins to delivery and 92% survival of at least one twin.[9] The authors, and others, postulate that deliberate septostomy results in an equilibration of amniotic fluid volumes around both twins as a result of hydrostatic pressure differences between the sacs that may be too small to measure. As in amnioreduction this technique does not directly address the postulated cause of TTTS, the transplacental vascular anastamoses, but offers temporizing measures in an attempt to prolong the pregnancy to the point where survival ex utero is possible.

FETOSCOPIC LASER ABLATION OF CHORIOANGIOPUS VESSELS (FLOC)


Fetoscopic laser ablation of chorioangiopagus vessels (FLOC) is the only proposed intervention for TTTS that directly addresses the postulated etiology of TTTS, that is, the transplacental vascular communications. This technique, first described by De Lia et al,[10] uses a fetoscopically-directed YAG-neodynium laser to photocoagulate those transplacental vascular communications felt to be contributing to the TTTS. Initial use of this technology involved ablation of all vessels crossing the vascular equator of the placenta, but more recently there has been more selective ablation involving only those vessels thought to be contributing to the TTTS. Data from recent series indicate 69% survival of both twins, 82% survival of at least one twin, and 4.3% significant handicap in survivors of an in-utero demise.[11]

 

2 survivors
At least 1 survivor
Spontaneous abortion
Double fetal loss
Neonatal death
Abnormal brain scan survivor(s)
Birth weight (donor)
Birth weight (recipient)

FLOC

42%
79%*
12%
3%*
6%
6%*
1750 g*
2000 g

Serial amnioreduction

42%
61%*
7%
19%*
14%
18%*
1145 g*
1560 g

  Table 2: Comparison of FLOC and amnioreduction.

CHOICE OF TREATMENT


Direct comparison of the efficacy of the different available interventions has not been accomplished. Comparisons extant in the TTTS literature typically compare case series using one intervention with case series using a different intervention. One such recent comparison [12] compared outcomes in 73 cases of severe TTTS treated with FLOC in one center with 43 cases of severe TTTS treated with serial amnioreduction in another center. (Table 2; * denotes p < 0.05)
There are currently two randomized trials underway in attempts to determine the most effective intervention for treatment of TTTS. One is the EUROFETUS consortium (www.eurofetus.org) that randomizes cases diagnosed with severe TTTS between serial amnioreduction and FLOC. The other trial is coordinated at the University of North Carolina [13] and is randomizing between serial amnioreduction and septostomy. The relatively infrequent nature of severe TTTS cases near any one center, and the (usually) strongly held opinions of a given treatment team has rendered recruitment into these trials more time-consuming than might have been originally anticipated.
Timing the intervention is of paramount importance in the treatment of TTTS. As in any medical procedure, the risks of the procedure itself must be weighed against the risk of the disease that is being treated. The known risks of any of the interventions for TTTS (preterm premature rupture of membranes, infection, preterm labor, placental abruption, hemorrhage and fetal death) must be acknowledged in deciding when to intervene. Quintero et al [14] presented a classification schema based on their experience (Table 3.) The group recently published their results following FLOC using their staging schema.[15] (Table 4.)

COMPLICATIONS OF TTTS


Consideration of the morbidity following diagnosis and treatment of TTTS is of equal importance to survival. In cases of TTTS treated with serial amnioreduction that are complicated by in-utero demise of one twin, neurological handicap is seen in approximately 30% of survivors [16]. Cases of TTTS treated with FLOC that are complicated by in-utero demise of one twin experience neurological handicap in 4.2% [17] (compared with the 18% incidence of neurological handicap seen in singleton survivors following serial amnioreduction.[12]. Taken at face value, these data suggest that while overall survival appears to differ little between the different interventions, there is a lesser risk of neurologic morbidity in survivors following FLOC than in survivors following serial amnioreduction.
There have also been reports of limb reduction anomalies and intestinal atresia associated with TTTS. Table 5 summarizes published cases of structural anomalies associated with monochorionic twinning. The etiology of these defects remains unclear. Hecher et al [18] suggested that polycythemia and an arterial steal syndrome were the probable etiology of necrotic toes detected prior to FLOC for severe TTTS. Margono et al [19] suggested that their findings of thrombosis of the transplacental vascular connections and necrosis of the right foot of the surviving twin were consistent with a thromboembolic phenomenon. Lundvall et al [20] found necrosis in the right lower leg of the recipient twin 27 days after FLOC. Post mortem examination found a thrombus in the right common iliac artery, "presumably the result of polycythemia". Scott and Evans [21] documented a case of severe TTTS managed with serial amnioreduction that resulted in 2 live twins. At time of delivery the recipient twin was found to have left lower leg necrosis that was associated with polycythemia (Hb 26.8 g/dL, Ht 89%). The authors concluded that the necrosis was the result of hyperviscosity due to polycythemia. Dawkins et al [6] reported a pregnancy with severe TTTS managed with amnioreduction x 6 over a nine week period. Delivery was at 32 weeks. The recipient twin was born with Hb 25.9 g/dL, Ht 72% and gangrene of the left lower leg. Arul et al [22] presented two cases of severe TTTS treated with FLOC. In both cases there was demise of the donor twin and in both survivors ileal atresia was noted after birth. The authors suggest three possible etiologies for these findings: hypoperfusion or hyperviscosity associated with TTTS could cause mesenteric ischemia; death of the donor could affect the hemodynamics of the survivor, causing mesenteric hypoperfusion; a shower of emboli or thromboplastins could be released into the fetal circulation. Van Allen et al [23] described two sets of monochorionic twins. The first case documented a singleton demise at 12 weeks EGA. At birth the surviving twin had cleft lip and palate and terminal limb reduction with ring constrictions of the left hand and both feet. In the other case singleton demise was documented at 18 weeks EGA. At birth the survivor was found to have ring constrictions of the left hand digits and left big toe. There was no evidence of amniotic bands in either case. The authors suggest that these findings were the result of vascular disruption in the co-twin. In our case TTTS was first diagnosed at 14 weeks and was treated with serial amnioreduction x 7. FLOC was performed at 23+ weeks EGA. Preterm premature rupture of membranes occurred at 26+ weeks EGA and cesarean delivery was at 28+ weeks. At time of delivery necrosis of the left lower extremity of the recipient was seen. The toe-heel length of the necrotic limb of 3.2 cm is consistent with 19 weeks 4 days gestation, which is prior to either the FLOC or the amnioreductions. Polycythemia was not universally seen in these cases, but is the most common finding among these pregnancies with severe TTTS affected with structural anomalies. Polycythemia could result from the elevated atrial natriuretic protein found in recipient twins and the resulting diuresis, and would lead to hyperviscosity. This hyperviscosity would result in greater incidence of thrombosis. It remains unclear why the lower extremities are more affected by such a thrombotic diathesis.

CONCLUSION


Monochorionic twins present unique challenges above and beyond those associated with multiple gestation. There have been several developments in the evaluation and treatment of twin-twin transfusion syndrome, but these twins remain at high risk. In spite of these advances, these twins are at continued risk for anomalies that appear to result from hypoperfusion. These anomalies have been seen in monochorionic twins that have undergone serial amnioreductions, FLOC or no intervention at all. This suggests that the tendency towards these defects is intrinsic to monochorionic twins suffering from TTTS, and is not related to the interventions that have been used in attempts to mitigate the impact of TTTS. The care of monoamniotic twins affected by TTTS continues to require coordinated care by a team of highly trained individuals.

REFERENCES

1. Robertson EG, Neer KJ. Placental injection studies in twin gestation. Am J Obstet Gynecol. 1983;147:170-4.
2. Blickstein I. The twin-twin transfusion syndrome. Obstet Gynecol 1990;76:714-21
3. Urig MA, Clewell WH, Elliott JP. Twin-twin transfusion syndrome. Am J Obstet Gynecol 1990;163:1522-6.
4. Cincotta RB, Gray PH, Phythian G, Rogers YM, Chan FY. Long term outcome of twin-twin transfusion syndrome. Arch Dis Child Fetal Neo 2000;83:F171-F176.
5. Pharaoh POD, Adi Y. Consequences of in-utero death in a twin pregnancy. Lancet 2000;355:1597-1602.
6. Dawkins RR, Marshall TL, Rogers MS. Prenatal gangrene in association with twin-twin transfusion syndrome. Am J Obstet Gynecol 1995;172:1055-7.
7. Mari G, Detti L, Oz U, Abuhamad A. Long term outcome in twin-twin transfusion syndrome treated with serial aggressive amnioreduction. Am J Obstet Gynecol 2000;1183:211-7.
8. Moise KJ. Polyhydramnios: problems and treatment. Semin Perinatol 1993;17:197-209.
9. Saade GR, Belfort MA, Berry DL, Bui T-H, Montgomery LD et al. Amniotic septostomy for the treatment of Twin Oligohydramnios-Polyhydramnios sequence. Fetal Diagn Ther 1998;13:86-93.
10. De Lia JE, Cruikshank DP, Keye WR. Fetoscopic laser occlusion of chorioangiopagus vessels in severe twin transfusion syndrome. Obstet Gynecol 1990;75:1046-53.
11. De Lia JE, Kuhlmann RS, Lopez KP. Treating previable twin-twin transfusion syndrome with fetoscopic laser surgery: outcomes following the learning curve. J Perinat Med 1999;27:61-7.
12. Hecher KH, Plath H, Bregenzer T, et al. Endoscopic laser surgery versus serial amniocenteses in the treatment of severe twin-twin transfusion syndrome. Am J Obstet Gynecol 1999;180:717-24.
13. Dorman K, Saade GR, Smith H, Moise KJ. Use of the world wide web in research: randomization in a multi-center clinical trial of treatment for twin-twin transfusion syndrome. Obstet Gynecol 2000;96:636-9.
14. Quintero RA, Morales WJ, Allen MH, Bornick PW, Johnson PK, Kruger M. Staging of Twin-twin transfusion syndrome. J Perinatol 1999;19:550-5.
15. Quintero RA, Morales WJ, Allen MH, Bornick PW, Johnson PK, Kruger M. Staging of Twin-Twin Transfusion syndrome. Frontiers in Fetal Health 2000;2:10-16.
16. Mahoney BV, Petty CN, Nyberg DA, Luthy DA, Hickock DE, Hirsch JH. The "stuck twin" phenomenon: ultrasonic findings, pregnancy outcome and management with serial amniocenteses. Am J Obstet Gynecol 1990;163:1513-22.
17. Ville Y, Hecher K, Gagnon A, et al. Endoscopic laser coagulation in the management of severe twin-to-twin transfusion syndrome. Br J Obstet Gynaecol. 1998;105:446-53.
18. Hecher K, Ville Y, Nicholaides K. Umbilical artery steal syndrome and distal gangrene in a case of twin-twin transfusion syndrome. Obstet Gynecol 1994;83:862-5.
19. Margono F, Feinkind L, Minkoff HL. Foot necrosis in a surviving fetus associated with twin-twin transfusion syndrome and monochorionic placenta that received no intervention. Obstet Gynecol 1992;79:867-9.
20. Lundvall L, Skibsted L, Graem N. Limb necrosis associated with twin-twin transfusion syndrome treated with YAG-laser coagulation. Acta Obstet Gynecol Scand 1999;78:49-50.
21. Scott F, Evans N. Distal gangrene in a polycythemic recipient fetus in twin-twin transfusion. Obstet Gynecol 1995;86:677-9.
22. Arull GS, Carroll S, Soothill PW, Spicer RD. Intestinal complications associated with twin-twin transfusion syndrome after antenatal laser treatment: report of two cases. J Pediatr Surg 2001;36301-2.
23. Van Allen MI, Siegel-Bartelt J, Dixon J, Zuker RM, Clarke HM, Toi A. Constriction bands and limb reduction defects in two newborns with fetal ultrasound evidence for vascular disruption. Am J Med Genet 1992;44:598-604.

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