Twin-Twin Transfusion Syndrome / TTTS
Fetal Surgery for Twin-Twin Transfusion Syndrome / TTTS
TTTS Diagnostic Criteria | TTTS Treatment Options | References | Contact Us / Request an Appointment
Twin-twin transfusion syndrome / TTTS, or oligohydramnios / polyhydramnios sequence, is a rare syndrome that occurs at an estimated rate of 0.1 to 0.9 per 1000 births.
This diagnosis carries an extremely poor prognosis, and it may be responsible for 15% to 17% of all perinatal deaths in twins.
TTTS occurs usually in the setting of monochorionic gestations and rarely in dichorionic twins when vascular connections between the 2 placentas exist.
It is estimated that 85% of monochorionic placentas have anomalous vascular connections; however, only 5% to 10% have sufficient imbalance to produce the TTTS. It is also believed that the number of vascular anastomoses and types of anastomoses within a placenta determine if TTTS develops.
The natural history of TTTS is associated with a 60% to 100% mortality for both twins in the most severe cases. The most severely affected fetuses usually present with signs of TTTS before 20 weeks' gestation.
Mothers commonly present clinically after 20 weeks' gestation with an acute increase in abdominal girth, discomfort and occasionally respiratory compromise or preterm labor. Physical examination reveals tense polyhydramnios. However, presentation before 20 weeks' gestation is usually asymptomatic, and diagnosis is usually a serendipitous finding on routine ultrasound.
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Diagnostic criteria for Twin-Twin Transfusion Syndrome / TTTS include:
- Monochorionicity (chorionicity is best determined in the first trimester and is more difficult to determine in the second trimester)
- A marked discordance in amniotic fluid volume between the twins (thus the term oligohydramnios / polyhydramnios sequence)
- A size discordance with the larger twin in the polyhydramniotic sac (except in TTTS presenting before 20 weeks' gestation, in which size discordance may not be pronounced)
- Same-sex twins and a single placental mass
The most characteristic feature is the presence of a "stuck twin," in which the larger recipient twin has a large bladder and a polyhydramniotic sac and a smaller donor twin has a small bladder and is stuck against the uterine wall in an oligohydramniotic sac.
A stuck twin can occur from causes other than TTTS, including:
- Premature rupture of membranes
- Placental insufficiency
- Urinary tract or other structural abnormalities
- Chromosomal anomalies
- Infectious etiologies
Initially, the twins present on ultrasound with a growth discrepancy between the larger recipient twin and the growth-restricted donor twin. It is not uncommon for the donor twin to have a velamentous placental cord insertion, which may exacerbate the growth discrepancy.
The volume stress on the recipient heart in TTTS often leads to cardiac changes. The recipient may develop cardiomyopathy with ventricular dysfunction that culminates in fetal hydrops. These cardiac changes include:
- Ventricular hypertrophy
- Tricuspid valvular insufficiency
- In advanced cases, an akinetic right ventricle and pulmonic valvular insufficiency or atresia.
Co-twin demise (usually the recipient) may occur as the fetal hydrops worsens. The surviving twin is at risk for severe neurologic injury caused by vascular resistance changes and consequent ischemic neurologic events. The surviving co-twin is also at risk for concomitant demise in at least 4% to 10% of cases and may be as high as 50% of cases.
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Several treatment options exist for TTTS, including:
- Medical therapy
- Serial amnioreduction
- Amniotic septostomy
- Fetoscopic approaches
Experience with medical therapy has been anecdotal, with case reports of resolution of TTTS with either digoxin or indomethacin therapy. These therapies have not been widely accepted or applied in patients diagnosed with TTTS.
Serial amnioreduction is one of the most commonly used and widely accepted therapies for TTTS. Its mechanism of action is unknown, but it appears to prolong gestation in addition to improving uteroplacental blood flow.
Advocates of this therapy believe that amnioreduction increases the survival rate when compared with the natural history of TTTS and shows comparable survival to that observed with laser therapy. The major criticism of amnioreduction is that it may not prevent the neurologic complications of TTTS.
Amniotic septostomy has been intentionally performed in a small number of cases. Proponents of amniotic septostomy report equilibration of amniotic fluid volumes between the two fetuses that lasts for the duration of the pregnancy.
Although the mechanism of amniotic septostomy is unclear, its success may be related to its effects on fetoplacental hemodynamics. Amniotic septostomy may allow amniotic fluid to cross into the stuck twin's sac, resulting in a fluid bolus as the amniotic fluid is imbibed by the fetus. It is likely that restoration of amniotic fluid volume after just one or two amnioreductions is successful because of unintentional and unrecognized septostomy.
An interesting observation is that TTTS does not seem to occur in monochorionic monoamniotic pregnancies, perhaps for the samereason that amniotic septostomy works. However, as with serial amnioreduction, amniotic septostomy would not be expected to prevent the neurologic sequelae in the event of either co-twin demise.
In addition, if too large a septostomy is created, the twins are at risk for cord entanglement. Because of this risk, a microseptostomy is created, which is only a series of needle punctures of the intertwin membrane. Saade et al, recently reported the results of a prospective randomized trial comparing amnioreduction to septostomy.
The survival in each group was 65%, however no data on neurologic outcome was provided.
Fetoscopic laser as a treatment for TTTS was initially described by DeLia and colleagues in 1990. Experimental work in both sheep and monkey models showed the efficacy of fetoscopic laser photocoagulation by using a neodymium:yttrium-aluminum-garnet laser before its use in the first three human cases was reported in 1990.
The three women were treated at 18.5, 22, and 22.5 weeks of gestation after presenting with acute polyhydramnios. Two of the three procedures went uneventfully, but the third was complicated by a placental vessel perforation.
The first two patients delivered at 27 and 34 weeks' gestation because of premature rupture of membranes. The third patient developed severe preeclampsia at 29 weeks' gestation, necessitating delivery. Four of the six infants survived.
A follow-up to these initial cases was published in 1995. DeLia and colleagues reported 26 patients treated by a fetoscopic laser. The inclusion criteria were ultrasonographic findings consistent with TTTS, posterior placenta, gestational age younger than 25 weeks, and clinical polyhydramnios.
The treated patients had a mean gestational age of 20.8 weeks (range, 18 to 24 weeks). One patient had surviving triplets, eight had surviving twins, nine had a single survivor (two neonatal and seven fetal deaths), and eight had no survivors (all had pregnancy loss within 3 weeks of the procedure).
Surviving fetuses were delivered for obstetric reasons at a mean of 32.2 weeks (range, 26 to 37 weeks). Fifty-three percent (28 of 53) of fetuses survived, with 96% (27 of 28) showing normal development at a mean of 35.8 months of follow-up (range, 1 to 68 months).
A similar experience was reported by Ville and associates. Forty-five women were treated at a median gestational age of 21 weeks (range, 15 to 28 weeks). The rate of fetuses surviving to delivery was also 53%.
Among the survivors, the median gestational age at delivery was 35 weeks (range, 25 to 40 weeks), with a median interval between treatment and delivery of 14 weeks (range, 0 to 21 weeks). All of the survivors were developing normally at a median age of 12 months (range, 2 to 24 months).
Bajoria and coworkers argued that the vessels on the chorionic plate are only part of the chorioangiopagus and that more vascular connections occur deep within the cotyledons of the placenta.
Quintero and coworkers described the selective technique of fetoscopic laser photocoagulation for TTTS to address these deep communications. The placental surface is fetoscopically inspected for what he terms nonparticipating vessels and truly participating vessels as well as the location of the intertwin membrane.
Nonparticipating vessels occur in pairs with an artery entering a cotyledon and a vein returning to the same umbilical cord. In contrast, vessels truly participating in the TTTS are unpaired.
An artery leaving the umbilical cord of the donor enters a cotyledon, but there is no vein returning to donor umbilical cord; rather, a vein draining this cotyledon can be seen on the other side of the vascular equator heading back to the umbilical cord of the recipient fetus.
It is unlikely, however, that sufficient pressure changes could be transmitted across these deep communications within the cotyledons to account for the ischemic injury seen in surviving co-twins on fetal demise.
Although these deep vessels may contribute to TTTS, they are unlikely to be responsible for all of its morbidity. It is for that reason that these unpaired vessels, along with any direct artery-to-artery, or vein-to-vein communications on the chorionic plate, are selectively laser photocoagulated.18
A recent report from Germany compared outcomes of selective fetoscopic laser photocoagulation with those of serial amnioreduction for TTTS.
Unlike the technique described by DeLia, in which all vessels crossing the intertwin membrane are photocoagulated, the selective technique selects only those vessels for coagulation that appear to connect the circulations of the twins. These connections may be:
- Artery to vein
- Vein to vein
- Aartery to artery
- Connections within the placenta in which a cotyledon is perfused by an artery from one twin but drains by a vein returning to the other twin.
Seventy-three women were treated between 1995 and 1997 in one center by fetoscopic laser photocoagulation, and 43 patients were treated at another center between 1992 and 1996 by serial amnioreduction.
Women treated by fetoscopic laser instead of serial amnioreduction had:
- A higher proportion of pregnancies with greater than one survivor (79% versus 60%), a lower number of spontaneous intrauterine fetal deaths (3% versus 19%)
- A lower incidence of abnormal ultrasonographic findings in the brains of surviving neonates (6% versus 18%)
- An older gestational age at the time of delivery (33.7 versus 30.7 weeks)
Based on this information, the authors concluded that fetoscopic laser photocoagulation is a more effective treatment for TTTS than serial amnioreduction.
A study of the long-term follow-up of the cohort of patients undergoing fetoscopic laser from this series found that despite the low incidence of abnormalities on neonatal head ultrasound in these patients there was a significant incidence of neurodevelopmental abnormalities.
The neurodevelopmental problems were severe in 11% including cases of mental retardation, hemiplegia and quadraplegia. Moderate neurodevelopmental problems occurred in an additional 11%.
All of the treatment strategies for TTTS discussed above have evidence from retrospective, single center, or prospective but non-randomized studies suggesting that they improve survival. It is not clear, however, which therapy is best under what circumstances. In most centers in the United States the current standard of care is serial amnioreduction.
Microseptostomy is available in relatively few centers, despite the recent prospective randomized trial demonstrating efficacy equivalent to serial amnioreduction. Fetoscopic laser photocoagulation is available in only a few centers and the lack of controlled trials has limited enthusiasm for this more invasive therapy.
At present, it is not known which therapy for TTTS is best for specific patients, for either survival or neurodevelopmental outcome.
There are currently two prospective randomized clinical trials, the Eurofetus trial in Europe led by Yves Ville and the National-Institutes-of-Health-sponsored trial in the United States, led by Timothy Crombleholme. These trials both compare aggressive serial amnioreduction to fetoscopic laser photocoagulation.
The results of the Eurofetus trial were recently published and demonstrate a survival advantage in the arm of the study treated by fetoscopic laser. However, the results in both arms of the study had lower survival that was expected. The amnioreduction arm of the trial had a survival of only 39% which is the second lowest survival ever reported for amnioreduction in the treatment of twin-twin transfusion syndrome.
Reports from the large international registries and the prospective randomized trial comparing amnioreduction to septostomy consistently reported survival in the 62 to 65% range. The amnioreduction arm of the Eurofetus trial had a disproportionate number of terminations of pregnancy (n=17) compared to none in the fetoscopic laser treated arm of the study.
In addition, it is not clear that a standardized approach for aggressive amnioreduction was used in all centers in the trial. In the fetoscopic laser arm of the Eurofetus trial the survival was only 56%. Also much less than was anticipated.
The survival in the fetoscopic laser arm of the trial is consistent with reported survival using non-selective fetoscopic laser of 53%. It is less that the 65-70% reported survival with selective fetoscopic laser. Similarly, a "neurologic" outcome was reported at 6 months of age which reflects only the results of neuroimaging from head ultrasound or MRI and not neurodevelopmental outcome.
The survivors in the laser treated arm had a lower incidence of abnormalities on imaging studies compared to patients treated by amnioreduction. However, abnormalities detected on head ultrasounds or MRI do not necessarily predict neurodevelopmental outcome. Similarly, normal findings on head ultrasound or MRI do not insure a normal neurodevelopmental outcome.
The twin-twin transfusion syndrome trial sponsored by the National Institutes of Health (NIH) will correlate the results of serial prenatal ultrasounds, fetal echocardiographs and fetal MRIs with treatment by blinded reviewers.
In addition to the primary endpoint of the recipient and donor twin survival, the NIH sponsored trial will evaluate neonatal co-morbidities and most importantly correlate neuroradiologic findings with neurodevelopmental outcomes at 18-22 months by evaluation at centers in participating NICHD Neonatal Network. The NICHD Neonatal Network is devoted to the neurodevelopmental assessment of former premature infants.
It is hoped that these prospective randomized clinical trials will, for the first time, address in rigorous fashion many of the questions that remain unanswered about the treatment of severe TTTS.
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