Twin-to-Twin Transfusion Syndrome

Etiology

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 AV anastomoses and result in the shunting of blood towards 1 twin and away from the other when the AV anastomoses are unbalanced. Arterioarterial anastomoses and venovenous anastomoses can have bidirectional flow and are found more superficially on the placenta. AA anastomoses are considered protective against TTTS and are decreased in twin gestations with TTTS. MCMA twins are thought to have more AA anastomoses, which is a theoretical reason why rates are lower in these twins than in MCDA twins.[4] 

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. The hypervolemia experienced by the other twin causes cardiac stretch, which increases atrial natriuretic peptide and brain natriuretic peptide release in that twin. This inhibits the renin-angiotensin-aldosterone system and leads to polyuria and polyhydramnios.[5][6][7] 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.[8]

Epidemiology

It is estimated that twin births account for about 2% to 4% of births worldwide.[9] Based upon data from the National Vital Statistics System of the National Center for Health Statistics of the Centers for Disease Control and Prevention, the prevalence of twin births in the United States in 2018 was about 33 per 1000 live births or about 3% of live births.[10] This is an increase in twinning rate from about 1.8% in the U.S. in 1980.[9]  Of twin gestations, an estimated 67% are dizygotic, and 33% are monozygotic. Among monozygotic twins, approximately 75% are MCDA. TTTS occurs at a rate of about 8-10% of MCDA twin gestations, about 6% of MCMA twin gestations, and it is estimated that 1 to 3 per 10,000 births are affected by TTTS.[1][4] As there is a possibility of monozygotic twinning with in vitro fertilization, TTTS can also occur in such pregnancies. There is little data regarding the prevalence of each stage of TTTS. Based upon data from referral centers, the Society for Maternal-Fetal Medicine (SMFM) estimates a prevalence of Stage I: 11% to 15%, Stage II: 20% to 40%, Stage III: 38% to 60%, Stage IV: 6% to 7%, and Stage V: 2%.[1]

History and Physical

The physical findings of the fetuses expected of this disease depend upon the stage of TS. Still, at the very least, they must include oligohydramnios in 1 amniotic sac and polyhydramnios in the other. As mentioned above, in monoamniotic gestations, polyhydramnios are seen in the amniotic sac and differences in the fetal bladders.[4] In cases of significant oligohydramnios, the amnion surrounding the donor twin can appear “stuck” to the twin on ultrasound.[3]

Mothers may experience no symptoms, symptoms before TTTS is diagnosed, and/or symptoms after TTTS is diagnosed.[11] In a survey of women who had a pregnancy complicated by TTTS, symptoms were experienced by almost half of these women before their diagnosis. Rapid weight gain, a feeling of swelling, and pain were the most common symptoms experienced by these women, followed by contractions and “other.”

Evaluation

Based upon the SMFM Guideline on TTTS, an ultrasound at 10 to 13 weeks evaluating viability, chorionicity, crown-rump length, and nuchal translucency is recommended for women with twin gestation. Future development of TTTS is associated with the crown-rump length and nuchal translucency abnormalities. Additional ultrasound findings that are associated with TTTS include velamentous umbilical cord insertion and intertwin membrane folding. Once MCDA twin gestation is established, it is recommended that women return for ultrasound scanning every 2 to 4 weeks to monitor for the development of TTTS, which typically develops in the second trimester and is usually seen between 16 and 26 weeks.[4] 

At 16 weeks, it is recommended to begin performing an ultrasound to assess the maximal vertical pocket in each amniotic sac as well as fetal bladders with repeat scans every 2 weeks until delivery. This scanning frequency is recommended due to the variability in progression to TTTS. Delivery timing differs depending upon individual characteristics of each pregnancy complicated by TTTS, including stage and intervention effects; thus, considering these characteristics, SMFM recommends delivery timing around 34 to 37 weeks if possible. To promote fetal lung maturation, SMFM also recommends considering steroids between gestational ages of 24 to 34 weeks, especially due to the higher risk of preterm birth in this population.

Limited data demonstrate the benefit of utilizing Doppler studies of the umbilical artery as a screening tool for TTTS. Still, the SMFM states it can be used when a size and/or fluid discrepancy is noted. Doppler studies of the umbilical artery, umbilical vein, and ductus venosus in each twin help establish staging once TTTS is diagnosed. SMFM also recommends fetal echocardiography in MCDA twin gestations due to the increased risk of congenital heart disease in this population, especially in gestations with TTTS, which negatively affects the recipient twin’s heart. Due to the increased risk of preterm labor and miscarriage in both twin gestations and TTTS, in addition to shortened cervix occurring in about 6% to 7% of pregnancies complicated by TTTS, evaluating the cervix length has also been recommended.[3] Counseling for the mother and her partner is recommended.[1]

Treatment / Management

There are multiple management options available once TTTS is diagnosed. These include expectant management, amnioreduction, intentional septostomy (not commonly performed currently), fetoscopic laser photocoagulation, selective reduction, and voluntary pregnancy termination. Amnioreduction is typically performed to correct the polyhydramnios to < 8 cm, can be performed at any point > 14 weeks, and can be performed once or serially. Selective reduction is not considered unless the TTTS has reached stage III or IV.

Fetoscopic laser photocoagulation is performed under ultrasound guidance, typically between 15 to 26 weeks of gestation, to create “2 chorions,” each supplying 1 twin. The procedure can be completed outside of this timeframe, but there are different disadvantages in these timeframes; at under 16 weeks, there is a greater risk of PPROM, and at over 25 weeks, there is greater difficulty in coagulation due to the increased size of vessels. It has been recommended that AV, AA, and VV anastomoses be selectively coagulated rather than nonselectively coagulated. However, there is concern that some anastomoses could be missed, resulting in a greater risk of recurrence of TTTS and twin anemia polycythemia sequence (TAPS). 

The Solomon technique was then developed, consisting of coagulating in a thin line from 1 end of the placenta to the other after finding and coagulating the anastomoses. This technique does result in fewer TTTS recurrences, decreased development of TAPS, and increased perinatal survival, but there is a greater risk of placental abruption. Based upon the available data, the authors of the 2019 Update on TTTS in Best Practice and Research Clinical Obstetrics and Gynaecology recommend a partial Solomon technique in which anastomoses are coagulated as well as a small area along the division of the placenta to optimize sufficient anastomoses coagulation and salvaging of a healthy placenta.[4] Management recommendations differ based on the stage of TTTS and gestational age and are outlined below:[1]

Stage I: Expectant management is recommended due to outcomes similar to amnioreduction and fetoscopic laser photocoagulation. Weekly ultrasound checks can be considered. Additionally, only about 25% of Stage I TTTS progresses in stage, and with expectant management, the survival of at least 1 twin occurs in most pregnancies.[12]

Stage II, III, IV: Fetoscopic laser photocoagulation is recommended at these stages at gestational age < 26 weeks.[1][4] A multicenter RCT conducted by Senat et al demonstrated better outcomes after fetoscopic laser coagulation than serial amnioreductions, including increased survival rates of 1 or both twins, delivery at greater gestational ages, and superior neurological outcomes.[4] It should be noted that this study did not include TTTS at Stage I and, thus, should not be applied to the management of that stage.

Stage V: No interventions have been evaluated at this stage.

Differential Diagnosis

Preterm premature rupture of membranes (PPROM) and premature rupture of membranes, amniotic fluid discrepancy caused by an anomaly in 1 twin, selective fetal growth restriction, and TAPS are in the differential diagnosis for TTTS. Before diagnosing TTTS, it is important to determine whether the mother has experienced a rupture of membranes by asking about any fluid leakage with or without contractions. sIUGR is defined by 1 twin displaying an estimated weight of < 10% based upon gestational age. Growth differences can occur as part of TTTS or separately from it. TAPS can occur spontaneously in MCDA twins (1% to 5%) or as a complication of fetoscopic laser photocoagulation (16%). Ultrasound findings prenatally include Doppler abnormalities in the MCA flow of both the donor and recipient twin, which indicate anemia in the donor and polycythemia in the recipient.[13]

Staging

The staging system most utilized for TTTS is the Quintero Staging System, which is based upon 2-dimensional ultrasound and Doppler study findings and is as follows:

• Stage I: oligohydramnios and polyhydramnios sequence, donor twin bladder is visible, doppler studies of UA/UV/DV are normal in both twins.
• Stage II: oligohydramnios and polyhydramnios sequence, donor twin bladder is not visible, doppler studies of UA/UV/DV are normal in both twins.
• Stage III: oligohydramnios and polyhydramnios sequence and abnormal Doppler study (only 1 of the following is required in either twin) [absent/reversed end-diastolic flow in UA, pulsatile flow in UV, or reversed a-wave flow in DV].
• Stage IV: oligohydramnios and polyhydramnios sequence; 1 or both fetuses have hydrops.
• Stage V: oligohydramnios and polyhydramnios sequence, and 1 or both fetuses have died.

Prognosis

Prognosis varies depending on the stage, the severity of the disease, and gestational age at diagnosis. Younger gestational age at diagnosis and the higher stage is 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, with overall survival of 86%. Additionally, about 75% of Stage I remain stable or regress.[12] There is less information available for Stages II-IV, but the perinatal death rate for ≥ Stage III is estimated to be 70% to 100%. Regarding Stage V, following the demise of 1 twin, there is a 10% risk of death and a 10 to 30% risk of neurological complication in the other twin. Some research shows an improved neurological outcome in the surviving twin if fetoscopic laser photocoagulation was performed earlier in gestation.

Complications

As mentioned above, the death of 1 or both twins is a complication of TTTS, with the survival of 1 twin ranging from 15% to 70% and the survival of both twins hovering around 50%. Cardiac complications can also occur in both the recipient and donor; these include atrioventricular valve insufficiency, diastolic dysfunction, pulmonary stenosis or atresia in the recipient, and vascular changes due to increased collagen synthesis and hypertrophy of the vascular media and smooth muscle layers in the donor.[8] In general, twin gestations have a higher risk of premature delivery, and there is similarly an elevated risk of premature delivery in TTTS. Neurological deficits are both complications of TTTS and preterm delivery, with an increased risk of cerebral palsy and long-term neurodevelopmental impairment (NDI).[14][13]

Complications also differ depending on management. Expectant management carries the complication risk of further stage progression; this risk of progression depends upon the stage at diagnosis as most (75%) of Stage I remain stable or regress without treatment.[12] Potential complications of amnioreduction include the death of 1 or both twins (survival rates following this procedure range from 50 to 65%), the need for serial amnioreductions, PPROM, preterm labor, placental abruption, infection, and decreased success of potential future fetoscopic laser photocoagulation. Additionally, there is an increased risk of poor neurological outcomes, including cerebral injury, cerebral palsy, and neurodevelopmental impairment after amnioreduction compared to fetoscopic laser photocoagulation.[14] While still the recommended treatment for Stages II-IV, fetoscopic laser photocoagulation has numerous possible complications, which consist of PPROM, preterm delivery, extravasation of amniotic fluid outside the uterus, placental abruption, vaginal bleeding, infection, fetal death, recurrent TTTS, and TAPS.[4] Although associated with a lower risk than amnioreduction, cerebral injury, cerebral palsy, and neurodevelopmental impairment are also potential complications of fetoscopic laser photocoagulation.[14]