Twin-to-Twin Transfusion Syndrome Imaging

Twin-to-twin transfusion syndrome (TTTS) is a common complication that typically presents in the second trimester of pregnancy in 10-15% of monochorionic (MC) twins due to net transfer of volume and hormonal substances from 1 twin to the other across vascular anastomoses on the placenta. Without recognition and treatment, TTTS is the greatest contributor to fetal loss prior to viability in 90-100% of advanced cases. ^[1]  The donor twin is small and anemic. The recipient twin is polycythemic, large, and at risk for high-output cardiac failure. Mortality is 40-90%, with both twins at risk.

Ultrasonography remains the cornerstone test in the diagnosis of TTTS. ^[2]  Guidelines from the Society for Maternal-Fetal Medicine (SMFM) recommend ultrasonography at 10 to 13 weeks to evaluate viability, chorionicity, crown-rump length, and nuchal translucency for women with twin gestation. To diagnose TTTS prenatally, ultrasound must show a single placenta, 1 twin with oligohydramnios, and 1 twin with polyhydramnios. Growth discordance and intrauterine growth restriction can occur but are not required for diagnosis of TTTS. ^[3]

Delivery time differs depending upon individual characteristics of each pregnancy complicated by TTTS, including stage and intervention effects. With awareness of these characteristics, the SMFM recommends delivery timing around 34 to 37 weeks, if possible. ^[3]  After birth, premature infants may need to undergo transcranial ultrasonography, as premature twins are susceptible to intraventricular hemorrhage and periventricular leukomalacia. The SMFM states that Doppler studies of the umbilical artery can be undertaken when a discrepancy in size and/or fluid is noted. Doppler studies of the umbilical artery, umbilical vein, and ductus venosus in each twin help establish staging once TTTS has been diagnosed. ^[3]

The SMFM also recommends fetal echocardiography in monochorionic diamniotic (MCDA) twin gestations due to increased risk of congenital heart disease in this population, especially in gestations with TTTS, which negatively affects the recipient twin’s heart. ^[3]  Echocardiography may depict myocardial dysfunction, myocardial hypertrophy, valvular insufficiency, and/or pericardial effusion in either twin. Renal ultrasonography may depict altered renal echogenicity, which indicates hypoxic-ischemic cortical necrosis. Infants with hydrops may need to be examined with abdominal sonography to detect ascites due to hydrops.

Conventional radiography has no role in the diagnosis or management of TTTS. A chest radiograph is sometimes required to detect pleural effusion and cardiomegaly in hydrops fetalis.

A retrospective cohort study of MCDA twin pregnancies complicated by TTTS that underwent laser coagulation of vascular anastomoses or fetal reduction by umbilical cord occlusion found that the prevalence of brain lesions detected by third-trimester MRI is higher than that of prenatal ultrasonography alone, making MRI a useful adjunct to detect antenatal brain lesions in twin pregnancies after in utero treatment for TTTS. ^[4] MRI is potentially useful in preoperative planning. Virtual navigation during fetal surgery is possible as a result of shortened MRI acquisition times and volume-rendering software.

Minimally invasive fetoscopic laser surgery is the standard and optimal treatment for this condition, but it is technically challenging and can lead to complications. Accurate preoperative planning is vital for complex TTTS cases. ^{[1, 5]}

Prognosis varies depending on disease stage and severity and gestational age at diagnosis. Younger gestational age at diagnosis and higher disease stage is associated with poorer prognosis. ^[3]  Preterm birth remains a significant contributor to postnatal morbidity and mortality. Long-term outcomes of TTTS survivors indicate that up to 11% of children may show signs of neurologic impairment. ^[1]

 (See the images below.)

 

 

Pathophysiology

The principal etiology of TTTS is an increased number of arteriovenous anastomoses deep in the placenta; these are capillary connections that occur in the cotyledon portion of the placenta. Unidirectional flow can occur in these arteriovenous (AV) anastomoses and can result in shunting of blood toward 1 twin and away from the other when AV anastomoses are unbalanced. The hypovolemia experienced by 1 twin causes renal hypoperfusion, which stimulates the renin-angiotensin-aldosterone system in that twin. This leads to oliguria and oligohydramnios. Atrioventricular valve insufficiency, diastolic dysfunction, and pulmonary stenosis or atresia can be seen in the recipient. In contrast, vascular changes due to increased collagen synthesis and hypertrophy of the vascular media and smooth muscle layers can be seen in the donor. ^[3]

Prompt identification of TTTS is of utmost importance; early diagnosis in fact is critical for effective treatment and management of TTTS. Because TTTS is a highly progressive condition, delay in diagnosis can result in disastrous outcomes; just a few weeks' delay in diagnosis of TTTS can lead to fatal outcomes for 1 or both twins. ^[6]

Epidemiology

It is estimated that twin births account for about 2-4% of births worldwide and about 3% of live births in the United States. Of twin gestations, an estimated 67% are dizygotic and 33% are monozygotic. Approximately 75% of monozygotic twins are monochorionic diamniotic (MCDA). Twin-to-twin transfusion syndrome occurs at a rate of about 8-10% among MCDA twin gestations and 6% among monochorionic monoamniotic (MCMA) twin gestations. It is estimated that 1-3 per 10,000 births are affected by TTTS. Twin-to-twin transfusion syndrome can occur in in vitro fertilization pregnancies. The SMFM estimates the following prevalence rates by stage: stage I, 11-15%; stage II, 20-40%; stage III, 38-60%; stage IV, 6-7%; and stage V, 2%. ^[3]

Prognosis

Prognosis varies depending on the stage and severity of disease and on gestational age at diagnosis. Younger gestational age at diagnosis and higher stage of disease are associated with poorer prognosis. Single twin survival ranges from 15 to 70%, with about 50% survival of both twins, even with treatment. The prognosis is best for stage I patients, with overall survival of 86%. Additionally, about 75% of stage I patients remain stable or regress. ^[3]

Without recognition and treatment, TTTS is the greatest contributor to fetal loss prior to viability in 90-100% of advanced cases. Contemporary outcome data after laser surgery suggest survival for both fetuses can be anticipated in up to 65% of cases, and survival of a single fetus in up to 88% of cases. However, preterm birth remains a significant contributor to postnatal morbidity and mortality. Long-term outcomes of TTTS survivors indicate that up to 11% of children may show signs of neurologic impairment. ^[1]

A collaborative cohort study of long-term indomethacin therapy for management of TTTS found that long-term indomethacin given for at least 48 hours after fetoscopic laser surgery for TTTS is effective in prolonging pregnancy and reducing risk for preterm birth, especially extreme preterm birth, among patients with TTTS. ^[7]

Treatment

Minimally invasive fetoscopic laser surgery is the standard and optimal treatment for TTTS, but it is technically challenging and can lead to complications. Acquiring and maintaining the necessary surgical skills require consistent practice and a steep learning curve. Accurate preoperative planning is vital for complex TTTS cases. ^{[1, 5]}

In a comprehensive usability study, Torrents-Barrena et al proposed the first TTTS fetal surgery planning and simulation platform, in which soft tissues of the mother, the uterus, the umbilical cords, and the placenta and its vascular tree are registered automatically from MRI and 3-dimensional (3D) ultrasound images using computer vision and deep learning techniques. This state-of-the-art technology is integrated into a flexible C++ and MITK-based application to allow full exploration of the intrauterine environment by simulating use of the fetoscope camera, along with laser ablation, determining the correct entry point, and training doctors' movements and trajectory ahead of operation. Experienced surgeons rated this TTTS planner and simulator highly as a potential tool to be implemented in real and complex TTTS surgeries. ^[5]

Once TTTS is diagnosed, many management options are available, including expectant management, amnioreduction, intentional septostomy (not commonly performed), fetoscopic laser photocoagulation, selective reduction, and voluntary pregnancy termination. Amnioreduction is typically performed to correct polyhydramnios less than 8 cm, can take place at any point after 14 weeks, and can occur once or serially. Selective reduction typically is not considered unless TTTS has reached stage III or IV. Between 15 and 26 weeks’ gestation, fetoscopic laser photocoagulation typically is performed with the goal of creating “2 chorions,” each supplying 1 twin. However, there is concern that some anastomoses could be missed and that risk of recurrence and of twin anemia polycythemia sequence (TAPS) may be increased. Thus, the Solomon technique was developed, which consists of coagulating a thin line from one end of the placenta to the other after anastomoses have been coagulated. This technique results in fewer TTTS recurrences, decreased development of TAPS, and increased perinatal survival, although risk of placental abruption is present, ^[3] leading Bamberg and Hecher to recommend use of a partial Solomon technique, in which anastomoses are coagulated, along with a small area along the division of the placenta, to optimize anastomosis coagulation and attainment of a healthy placenta. ^[8]

Management recommendations differ based on TTTS stage and gestational age ^[3] :

• Stage I: Expectant management
• Stage II, III, IV: Fetoscopic laser photocoagulation
• Stage V: No interventions evaluated at this stage

Staging of TTTS

The Quintero staging system appears to be a useful tool for describing the severity of TTTS in a standardized fashion. ^{[3, 9]}  The stages of TTTS defined by using the proposed criteria have prognostic significance. This staging system may allow for comparisons of TTTS outcome data versus different treatment modalities.

The Qunitero staging system is based on 2-dimensional ultrasound and Doppler study findings and is explained as follows ^[3] :

• Stage I: Oligohydramnios and polyhydramnios sequence, visible bladder in the donor twin, normal Doppler studies in both twins.

• Stage II: Oligohydramnios and polyhydramnios sequence, bladder in the donor twin no longer visible, no critically abnormal findings on Doppler studies.

• Stage III: Oligohydramnios and polyhydramnios sequence, abnormal Doppler study (only 1 of the following required in either twin: absent/reversed end-diastolic flow in umbilical artery [UA], pulsatile flow in umbilical vein [UV], reversed a-wave flow in ductus venosus [DV]).

• Stage IV: Oligohydramnios and polyhydramnios sequence, hydrops in 1 or both fetuses.

• Stage V: Oligohydramnios and polyhydramnios sequence, death of 1 or both fetuses.

The Society for Maternal-Fetal Medicine (SMFM) recommends fetal echocardiography in MCDA twin gestations due to increased risk of congenital heart disease in this population, especially among gestations with TTTS, which negatively affects the recipient twin’s heart. ^[3]  Echocardiography may depict myocardial dysfunction, myocardial hypertrophy, valvular insufficiency, and/or pericardial effusion in either twin.

Evaluating cervix length is recommended due to increased risk of preterm labor and miscarriage both in twin gestations and in TTTS, in addition to shortened cervix in about 6-7% of pregnancies complicated by TTTS. ^[3]  

Radiography

Conventional radiography has no role in diagnosis or management of TTTS. A chest radiograph is sometimes required to detect pleural effusion and cardiomegaly in hydrops fetalis.

Magnetic resonance imaging

In a retrospective cohort study of monochorionic diamniotic (MCDA) twin pregnancies complicated by TTTS, Aertsen et al found that the prevalence of brain lesions detected by third-trimester MRI is higher than that of prenatal ultrasonography alone, making MRI a useful adjunct to detect antenatal brain lesions in twin pregnancies after in utero treatment for TTTS. ^[4]

In another retrospective cohort study of women with monochorionic twin pregnancies who underwent laser ablation for TTTS, Hochberg et al sought to determine the rate of and risk factors for fetal and neonatal brain lesions following this intervention. These investigators reported that clinicians should consider incorporating neurosonography and fetal brain MRI into routine surveillance of such pregnancies, in which survivors of ablation for TTTS are at risk for brain lesions. ^[10]

Ultrasonography

The SMFM guidelines on TTTS recommend that women with twin gestation undergo ultrasonography at 10-13 weeks to evaluate viability, chorionicity, crown-rump length, and nuchal translucency. Future development of TTTS is associated with crown-rump length and nuchal translucency abnormalities. Once MCDA twin gestation is established, it is recommended that women return for ultrasound scanning every 2-4 weeks to  monitor for development of TTTS, which typically occurs in the second trimester and usually is seen between 16 and 26 weeks. ^[3]  

At 16 weeks, it is recommended that ultrasonography should be performed to assess the maximal vertical pocket (MVP) in each amniotic sac and repeat scans of fetal bladders obtained every 2 weeks until delivery. The SMFM states that Doppler studies of the umbilical artery can be used when a discrepancy in size and/or fluid is noted. ^[3]  

Ultrasonographic features of TTTS include the following ^{[2, 3]} :

• A single placenta, 1 twin with oligohydramnios, and 1 twin with polyhydramnios

  • Oligohydramnios defined as MVP < 2 cm
  • Polyhydramnios defined as MVP >8 cm
• Monochorionic twins with a single placenta, with visualization of a separating membrane
• Velamentous umbilical cord insertion
• Intertwin membrane folding
• Doppler abnormalities in middle cerebral artery (MCA) flow of both donor and recipient twins

  • Indicate anemia in the donor and polycythemia in the recipient

The Quintero staging system is based on 2-dimensional ultrasonography and Doppler study findings. ^[3]

Fetoscopic laser photocoagulation is performed under ultrasound guidance typically between 15 and 26 weeks’ gestation, with the goal of creating “2 chorions,” each supplying 1 twin. ^[3]

Renal ultrasonography may depict altered renal echogenicity, which indicates hypoxic-ischemic cortical necrosis. Infants with hydrops may need to be examined with abdominal sonography to detect ascites due to hydrops.

In a retrospective study, Brock et al assessed compliance with and effectiveness of fortnightly ultrasound surveillance for detection of TTTS in MCDA twin gestations. The surveillance protocol required fortnightly ultrasound studies starting at 16 weeks’ gestational age (GA) and continuing until delivery. Compliance was assessed by determining the GA of surveillance initiation and the time between ultrasounds. Gestational age and Quintero stage at diagnosis were evaluated to determine whether TTTS was detected before advanced disease (Quintero stage III+) or fetal demise. Investigators reported the following: Of 442 women, 264 (59.7%) initiated surveillance after 16 weeks; follow-up ultrasounds were late in 17.4% of cases. Twin-to-twin transfusion syndrome was diagnosed in 43 (9.7%) women at a median GA of 19.7 (range, 17.4-23.9) weeks. Among 25 of 43 (58.1%) cases diagnosed during protocol compliance, 12 had advanced disease and 2 had fetal demise. A similar proportion of diagnoses (n = 18), made while noncompliant, exhibited advanced disease (11/18, 61.1%; P = 0.40). Thirteen diagnoses occurred during periods of increased ultrasound frequency due to abnormalities (ie, fluid/estimated fetal weight discrepancies or Doppler abnormalities). Results show that in this population, fortnightly ultrasound compliance was suboptimal. Advanced disease and fetal demise occurred during protocol compliance. ^[11]

(See images below.)

Folding of the intertwin membrane occurs in about 25% of MC twins, ^[12]  and about half of these twins subsequently develop severe TTTS. Another finding is an abnormal Doppler systolic-diastolic (S/D) ratio at the umbilical cord, which shows absent end-diastolic flow in the donor's umbilical artery, accompanied by venous pulsation in the recipient's umbilical vein. This sign is usually associated with a poor prognosis. Antenatal detection of artery-to-artery anastomosis is predictive of improved perinatal outcomes and double survival in TTTS, independent of disease stage. ^[13]

Hydrops or evidence of congestive cardiac failure may be seen in either twin but is most common in the recipient twin.

The cocoon sign is present in at least 15% of patients with TTTS. Its recognition is important to prevent misdiagnosis of TTTS. The cocoon sign is diagnosed when sonograms show a donor twin with severe oligohydramnios that is enveloped by dividing membranes and is connected to the uterine wall by a laminar stalk of these membranes. ^{[14, 15]}

In TTTS, the recipient twin shows progressive biventricular hypertrophy with predominant right ventricular systolic and biventricular diastolic dysfunction. Despite amnioreduction, cardiovascular disease persists and even progresses in many recipient twins. ^{[16, 17]}

Degree of confidence

Sonography is useful in predicting placentation—a process that may be helpful in predicting fetal outcomes. In severe cases, the diagnosis of twin-to-twin transfusion syndrome (TTTS) is generally straightforward when imaging shows a single placenta with massive polyhydramnios in the sac of the recipient twin and a stuck donor twin attached to the uterine wall. Poor mobility and obvious growth discordance are often present. Mild forms may be difficult to diagnose because uniform criteria are lacking. However, this possibility should be suspected whenever the amniotic fluid differs between amniotic cavities, regardless of weight discordance between twins.

False positive diagnoses are possible with twin oligohydramnios-polyhydramnios sequences and dichorionic twin pregnancies with fused placentas and growth retardation.