Twin-Twin Transfusion Syndrome (TTTS)
1. What every clinician should know
Clinical features and incidence
Twin-twin transfusion syndrome (TTTS) is a condition that affects about 10% of monozygotic twins. Although the pathophysiology of TTTS is not completely understood, placental anastomoses that link the circulations of the twins are critical for its development. In affected pregnancies, blood flow in these anastomoses is unbalanced, with one twin, the donor, transferring a net volume to its co-twin, the recipient.
Most pregnant patients have few symptoms or signs that TTTS has developed but some may notice rapid abdominal distension, pelvic pressure or preterm contractions secondary to the increase in amniotic fluid volume that accompanies this condition. During office visits, greater than expected maternal weight gain or larger than anticipated symphysis-fundal height are hints of possible TTTS in women carrying a multiple gestation containing an identical twin pair.
TTTS occurs almost exclusively in monozygotic twins with monochorionic-diamniotic (MCDA) placentation. Identical twins with dichorionic or monoamniotic placentation rarely develop TTTS. Although monozygotic twinning is a sporadic event in spontaneous pregnancies, it is increased in pregnancies conceived by in vitro fertilization (IVF) and thus, TTTS is a risk in IVF multiple gestations. MCDA twins with an abnormal placental cord insertion (PCI), particularly velamentous, are more at risk of developing TTTS. (Figure 1)
Twin differences in crown-rump length, nuchal translucency, abdominal circumference and amniotic fluid volume may help to identify the subset of MCDA twins more likely to be subsequently diagnosed with TTTS. MCDA twin pairs with an abnormal Doppler waveform in the ductus venosus or abnormal peak systolic flow velocities in the middle cerebral arteries are also at increased risk of TTTS.
2. Diagnosis and differential diagnosis
Establishing the diagnosis
The diagnosis of TTTS is made by ultrasound so serial sonographic surveillance of MCDA twins is necessary to detect this condition in its earliest stages. Oligohydramnios-polyhydramnios sequence, the finding of low fluid in one sac and high fluid in the other sac, is essential for the diagnosis of TTTS. The twin with oligohydramnios often appears stuck in its sac, plastered against the placenta or uterine wall. TTTS has been categorized into five stages:
Stage I: maximal vertical pocket of amniotic fluid less than 2 cm in the donor sac and greater than 8 cm in the recipient sac. (Figure 2) (Figure 3)
Stage II: nonvisualization of the fetal bladder in donor twin for more than 60 minutes. (Figure 4)
Stage III: absent or reversed umbilical artery diastolic flow, reversed ductus venosus a-wave flow or pulsatile umbilical vein flow. (Figure 5)
Stage IV: fetal hydrops in one or both twins.
Stage V: fetal demise in one or both twins.
Doppler velocimetry of the middle cerebral arteries may demonstrate elevated peak systolic velocities in the donor twin suggesting fetal anemia and reduced peak systolic velocities in the recipient twin, implying polycythemia. Both fetal echocardiography and fetal MRI are ancillary studies that may provide additional information about the impact of TTTS on the twins. Cardiac dysfunction, biventricular hypertrophy and functional or structural right ventricular outflow obstruction may develop in the recipient twin over time. Central nervous system abnormalities such as hemorrhagic or ischemic changes have been detected in cases of TTTS, which carries a less favorable prognosis.
The differential diagnosis of TTTS is limited to conditions that cause oligohydramnios or polyhydramnios in a twin pregnancy with MCDA placentation. The most common condition to consider in such cases is unequal placental sharing with discordant twin growth. This affects 20% of MCDA twins and can result in oligohydramnios and a small or non-visualized bladder in the smaller twin. Discordant twin growth can coexist with TTTS; however, in the absence of TTTS the larger twin will have normal amniotic fluid volume.
Other conditions to consider in the differential diagnosis include oligohydramnios secondary to renal functional or obstructive anomalies, premature rupture of membranes, polyhydramnios due to fetal conditions that impair swallowing, or malformations obstructing the gastrointestinal tract or adversely affecting cardiac function. (Figure 6) These conditions can usually be excluded by a comprehensive anatomy scan of the twins and a clinical evaluation for membrane rupture. The finding of normal fluid in one sac precludes a firm diagnosis of TTTS while the detection of the oligohydramnios-polyhydramnios sequence in an MCDA twin pregnancy strongly suggests TTTS as the most likely diagnosis.
First trimester imaging is critical for the early detection of twins and accurate determination of chorionicity. Given the risk of TTTS in MCDA twins, serial sonographic surveillance is recommended every 2 weeks beginning in the second trimester. Management options for TTTS vary depending on gestational age and stage at time of diagnosis. These may include pregnancy termination, selective reduction of an anomalous, growth restricted, or hydropic co-twin, fetoscopic laser photocoagulation of inter-twin placental anastomoses, amnioreduction, expectant observation or delivery.
Most cases of TTTS are diagnosed in the second trimester and in continuing pregnancies with advanced stages of TTTS (II-IV), fetoscopic laser photocoagulation is currently considered the best therapeutic intervention to improve perinatal survival. This procedure is considered an option between 16-26 weeks gestation and is performed in conjunction with an amnioreduction to normalize the fluid in the recipient’s sac immediately after laser completion. The management of stage I TTTS is controversial, as only 10-30% of cases progress while most cases remain stable, resolve spontaneously or do not recur after a single amnioreduction. Further studies are necessary to determine if laser therapy should be used for early TTTS.
Following fetoscopic laser photocoagulation for advanced TTTS, serial sonographic surveillance is necessary to assess the twins’ response to treatment. In most cases, TTTS resolves with normalization of amniotic fluid volume in both sacs, visualization of the donor’s bladder and improvement in the recipient’s twin cardiac function. Umbilical artery Doppler studies may remain abnormal in the presence of coexisting unequal placental sharing with discordant twin growth, and in these cases, antenatal fetal testing should be incorporated into third trimester management. Serial ultrasound evaluation for recurrent TTTS, reversed TTTS, twin anemia-polycythemia sequence (TAPS) and unequal placental sharing is also recommended until delivery.
Uncomplicated MCDA twins are usually delivered at 36 weeks gestation and this is also a reasonable gestational age to deliver successfully treated cases of TTTS. Occasionally, acute TTTS can develop beyond the therapeutic window for laser and in these cases, management usually involves antenatal steroids if time permits, followed by delivery. Recurrent TTTS, reversed TTTS, TAPS and discordant twin growth usually mandate an earlier delivery, again after administration of antenatal steroids.
The route of delivery is dependent on a number of factors and an individualized approach is recommended. If criteria for a vaginal twin birth are met, a trial of labor may be considered. However, the majority of women treated with fetoscopic laser photocoagulation for TTTS undergo a cesarean delivery at a gestational age of 32-34 weeks.
Routine postpartum care should be provided with additional support if the twins have complications related to TTTS or prematurity. Instruction about nursing twins and pumping, if a prolonged NICU stay is anticipated, can be beneficial in the bonding process and in establishing successful breastfeeding. Emotional support is also invaluable for the patient who experiences an unfavorable perinatal outcome, particularly if it involves the loss of one or both twins. Periodic assessments for postpartum depression are critical when caring for such patients and counseling about the low recurrence risk in a subsequent pregnancy can be reassuring.
Complications as a result of the condition
The polyhydramnios associated with untreated TTTS can be accompanied by shortness of breath, abdominal distension and discomfort, uterine contractions, cervical shortening, premature rupture of membranes, and preterm birth, usually by cesarean delivery. For patients with early TTTS or beyond the therapeutic window for laser, amnioreduction may be used to ameliorate maternal symptoms and potentially extend the length of pregnancy.
Successful fetoscopic laser photocoagulation lowers the risk of an extremely preterm or abdominal birth, but for all twin pregnancies. Without intervention, advanced TTTS often results in death of one twin which is associated with a 10% risk of demise in the co-twin or a 10-30% of neurologic handicap if the twin survives. Although laser may decrease the danger, adverse neurologic outcome is a risk for all survivors of TTTS regardless of management.
Complications as a result of management
A number of complications may arise as a consequence of fetoscopic laser photocoagulation, including maternal or fetal bleeding, infection, inadvertent septostomy, chorioamnion separation, preterm premature rupture of membranes, death of one or both twins, and subsequent preterm labor and delivery. The most frequent procedure related complication is preterm premature rupture of membranes, which complicates about 10% of laser cases. Careful patient selection is important, as women with regular, painful contractions or a short or dilated cervix are not good candidates for laser therapy.
Mapping of the placenta and cord insertions is necessary to determine the best fetoscopic insertion site to limit risks of bleeding and inadvertent septostomy. The procedure may not be possible to complete due to technical difficulties, recurrent TTTS, reversed TTTS, or TAPS that might develop due to missed or unsuccessfully coagulated inter-twin anastomoses. The centrally located placenta located on the anterior uterine wall poses the greatest challenge to the fetoscopist, particularly if the stuck twin is positioned against the placenta obscuring the vascular equator.
5. Prognosis and outcome
The prognosis of TTTS is dependent on the gestational age at diagnosis, clinical stage and progression of disease. Early stage TTTS that presents beyond 26 weeks and does not progress tends to have a favorable outcome for both twins. However, the majority of advanced TTTS presents in the second trimester and the expected perinatal survival after laser therapy in these cases is 50-70%. Without treatment, perinatal mortality is 70-100% in advanced stages of TTTS. Of pregnancies treated with fetoscopic laser, both twins survive in 50% of cases, a single twin survives in 30% of cases, and there are no surviving twins in 20% of cases.
Although procedure-related twin loss is a recognized complication of fetoscopic laser photocoagulation, survival with neurologic handicap is a serious long-term sequelae of TTTS, with or without treatment. Interventricular hemorrhage, cystic periventricular leukomalacia and subsequent diagnosis of neurodevelopmental delay and cerebral palsy remain risks for survivors of TTTS. Overall, rates of long-term neurologic sequelae in laser-treated TTTS are 5-20%. Additional risks related to preterm delivery and prematurity may impact the long-term outcomes for the surviving twins of these complicated MCDA pregnancies.
The impact on maternal long-term health is minimal apart from implications of having a cesarean delivery and its implications on subsequent pregnancies and risk for adhesion formation, peritoneal inclusion cysts, bowel obstruction and difficult abdominal surgery in the future. The psychological consequences of having an identical twin pregnancy complicated by death of one or both twins, or neurologic handicap in one or both twins, are more difficult to quantify but an unfavorable outcome has the potential to impact long-term maternal mental health.
6. What is the evidence for specific management and treatment recommendations
Fisk, NM, Duncombe, GJ, Sullivan, MH. “The basic and clinical science of twin-twin transfusion syndrome”. Placenta. vol. 30. 2009. pp. 379-90. (A thorough review of TTTS.)
Lopriore, E, Ortibus, E, Acosta-Rojas, R, Le Cessie, S, Middelorp, JM. “Risk factors for neurodevelopmental impairment in twin-twin transfusion syndrome treated with fetoscopic laser surgery”. Obstetrics and Gynecology. vol. 113. 2009. pp. 361-6. (One of the largest reports on the neurologic outcome of TTTS pregnancies treated with laser.)
Quintero, RA, Morales, WJ, Allen, MH, Bornick, PW, Johnson, PK. “Staging of twin-twin transfusion syndrome”. Journal of Perinatology. vol. 19. 1999. pp. 550-5. (Original article describing staging of TTTS.)
Senat, MV, Deprest, J, Boulvain, M, Paupe, A, Winder, N. “Endoscopic laser surgery versus serial amnioreduction for severe twin-to-twin transfusion syndrome”. New England Journal of Medicine. vol. 351. 2004. pp. 136-44. (The first randomized trial demonstrating benefit of laser over amnioreduction for advanced TTTS.)
Simpson, LL. “SMFM Clinical Guideline: Twin-twin transfusion syndrome”. American Journal of Obstetrics and Gynecology. (Recent guideline developed by SMFM.)
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- Twin-Twin Transfusion Syndrome (TTTS)
- 1. What every clinician should know
- 2. Diagnosis and differential diagnosis
- 3. Management
- 4. Complications
- 5. Prognosis and outcome
- 6. What is the evidence for specific management and treatment recommendations