Twin-to-twin transfusion syndrome
Twin-to-twin transfusion syndrome (TTTS) is a rare but serious complication that arises in identical twin pregnancies where the fetuses share a single placenta (monochorionic diamniotic), causing an imbalance in blood flow between the twins through abnormal vascular connections known as anastomoses in the placenta.[1] In this condition, blood is shunted disproportionately from one twin, termed the "donor," to the other, the "recipient," resulting in hypovolemia, anemia, and growth restriction for the donor, while the recipient experiences hypervolemia, polycythemia, and potential cardiac strain or failure.[2] TTTS typically manifests in the second trimester and affects approximately 10-15% of monochorionic twin gestations, or about 1 in 3,000 to 10,000 live births overall.[1][3] The syndrome is characterized by stark disparities in amniotic fluid levels—oligohydramnios (reduced fluid) around the donor twin and polyhydramnios (excess fluid) around the recipient—which can lead to maternal complications such as preterm labor or uterine overdistension if untreated.[1] Diagnosis relies on serial ultrasound examinations starting around 16 weeks of gestation, revealing the "stuck twin" appearance of the donor (deepest vertical pocket of amniotic fluid <2 cm) and the fluid overload in the recipient (>8 cm), often accompanied by Doppler assessment of blood flow and fetal echocardiography to evaluate cardiac function.[1] Staging, based on the Quintero system, ranges from stage I (fluid imbalance without donor bladder issues) to stage V (intrauterine fetal demise of one or both twins), with stage IV involving hydrops fetalis in the recipient, guiding management decisions.[1] Treatment options depend on gestational age and severity, with expectant management suitable for early, mild cases (Stage I), while more advanced stages often require interventions like amnioreduction to relieve polyhydramnios or, preferably, fetoscopic laser photocoagulation to ablate the interconnecting placental vessels, which offers the highest survival rates of up to 70-80% for at least one twin when performed before 26 weeks.[1][3] Without intervention, TTTS carries a high mortality risk, with up to 80-100% loss of one or both twins in severe untreated cases, though advancements in fetal surgery have significantly improved perinatal outcomes and long-term neurodevelopmental prognosis for survivors.[1] Postnatally, affected twins may require blood transfusions for the donor, partial exchange transfusions or diuretics for the recipient, and close monitoring for complications like renal or neurological issues.[2]Pathophysiology
Placental Vascular Anatomy
Twin-to-twin transfusion syndrome (TTTS) arises in monochorionic diamniotic (MCDA) twin pregnancies, where monozygotic identical twins share a single placenta derived from a common chorionic sac but develop within separate amniotic sacs.[4] This placentation results from early embryonic splitting (between days 4 and 8 post-fertilization), leading to a fused placental structure with interconnected fetal circulations via vascular anastomoses.[5] Unlike dichorionic twins, who have separate placentas, the shared MCDA placenta predisposes to inter-twin blood exchange, which is typically balanced but can become unbalanced in TTTS.[6] Vascular anastomoses in MCDA placentas connect the circulations of the two fetuses and are classified into three main types: arterio-arterial (AA), veno-venous (VV), and arterio-venous (AV).[7] AA anastomoses link the umbilical arteries of both twins, while VV anastomoses connect the umbilical veins; both are superficial and located on the chorionic plate surface, enabling bidirectional blood flow.[7] AV anastomoses, the most common type, join an artery from one twin to a vein of the other within shared placental cotyledons and are unidirectional, directing blood from the arterial to the venous side due to hydrostatic pressure gradients.[7] Superficial AA and VV anastomoses facilitate compensatory bidirectional exchange, helping to equalize volume and pressure differences across the placenta in uncomplicated cases.[7] In contrast, deep AV anastomoses occur at the capillary level inside cotyledons, lacking direct visibility on the surface and promoting net unidirectional transfer if unopposed by superficial connections.[6] Vascular anastomoses are present in 95-99% of MCDA placentas, with AV found in nearly all (~90-99%), AA in 80-96% of uncomplicated cases (but only ~47% in TTTS), and VV in ~25-28%.[7][8] Approximately 5% of placentas lack any anastomoses, and unbalanced configurations—such as predominant AV without sufficient AA compensation—occur in 10-15% of MCDA pregnancies, predisposing to TTTS.[7][8]Blood Flow Imbalances
In twin-to-twin transfusion syndrome (TTTS), the primary mechanism of pathogenesis involves unidirectional blood shunting through arteriovenous (AV) anastomoses in the shared monochorionic placenta, directing blood from the donor twin to the recipient twin via low-resistance pathways at the villous capillary level.[1] This shunting occurs because AV connections lack pressure equilibration between the arterial and venous systems, favoring net flow from the higher-pressure donor arterial circulation to the lower-pressure recipient venous system, resulting in chronic volume depletion for the donor and overload for the recipient.[1] Arterioarterial (AA) anastomoses, which provide bidirectional superficial connections between the twins' arteries, play a compensatory role by allowing retrograde flow to balance AV shunts, but in TTTS cases, these are often absent, reduced in number, or insufficient to counteract the unidirectional AV transfer, leading to a persistent net transfusion imbalance.[1] Without adequate AA compensation, the AV-dominated vascular configuration fails to equalize inter-twin blood distribution, exacerbating the hemodynamic disparities.[9] The imbalances progress primarily as a chronic process, typically manifesting between 16 and 26 weeks of gestation, where sustained AV shunting causes gradual volume shifts rather than acute events, although rare acute imbalances can occur during labor.[9] This chronicity drives the oligohydramnios-polyhydramnios sequence, with the donor twin experiencing renal hypoperfusion and reduced urine output leading to oligohydramnios, while the recipient twin develops polyuria from hypervolemia, resulting in polyhydramnios.[1] Physiologically, the donor twin suffers anemia due to ongoing blood loss and hypovolemia, which decreases venous return and cardiac preload, while the recipient twin develops polycythemia and hypervolemia, increasing cardiac preload and afterload, often leading to myocardial hypertrophy, diastolic dysfunction, and atrioventricular valve regurgitation.[1] These circulatory alterations in the recipient further strain the heart, potentially progressing to congestive failure, whereas the donor's reduced afterload from hypovolemia contributes to vascular remodeling with increased collagen deposition.[9]Effects on Fetuses
In twin-to-twin transfusion syndrome (TTTS), the donor twin experiences chronic hypovolemia due to net blood loss through unbalanced arteriovenous anastomoses in the shared monochorionic placenta, leading to reduced organ perfusion and growth.[1] This hypovolemia activates the renin-angiotensin-aldosterone system, resulting in oliguria and subsequent oligohydramnios, which can manifest as the "stuck twin" phenomenon where the donor adheres to the uterine wall, increasing the risk of fetal demise in early stages.[1] Additionally, the donor develops intrauterine growth restriction from diminished nutrient and oxygen delivery, along with anemia due to ongoing blood transfer, and risks renal dysfunction from hypoperfusion, potentially leading to nonvisualization of the fetal bladder on ultrasound.[10] The recipient twin, conversely, suffers from hypervolemia and hypertension caused by excessive blood inflow, imposing significant cardiovascular strain.[10] This overload promotes polyuria through elevated levels of atrial and brain natriuretic peptides, culminating in polyhydramnios that heightens the risk of preterm labor for both twins.[1] Cardiac effects include cardiomegaly, biventricular hypertrophy, diastolic dysfunction, and atrioventricular valve regurgitation, which can progress to heart failure and hydrops fetalis in advanced cases.[10] Neurological injury in the recipient may arise from hemodynamic instability, including brain ischemia due to blood pressure fluctuations or ischemia-reperfusion cycles during acute shunting episodes.[11] Both twins share vulnerability to twin anemia-polycythemia sequence (TAPS) as a related complication, where chronic intertwin hemoglobin differences persist or emerge post-intervention, exacerbating anemia in the donor and polycythemia in the recipient.[10] In severe TTTS, fetal demise often occurs via acute decompensation, with the recipient succumbing to cardiovascular collapse or the donor to profound hypovolemia, potentially triggering exsanguination or embolization in the survivor.[1]Clinical Presentation
Recipient Twin Features
The recipient twin in twin-to-twin transfusion syndrome (TTTS) experiences chronic volume overload due to arteriovenous shunting from the donor twin through placental vascular anastomoses. This hypervolemia leads to polyuria and subsequent polyhydramnios, characterized by a maximal vertical amniotic fluid pocket exceeding 8 cm, resulting in an enlarged amniotic sac that contrasts with the oligohydramnios in the donor's sac, as observed on prenatal imaging. Cardiovascular manifestations are prominent in the recipient twin, reflecting the strain from hypervolemia and hypertension. The heart often enlarges (cardiomegaly), with evidence of atrioventricular valve insufficiency, including tricuspid regurgitation and diastolic dysfunction. Abnormal Doppler ultrasound flows further indicate cardiac stress, such as reversed end-diastolic flow in the ductus venosus or pulmonary valve stenosis. Initially, the recipient twin may appear larger than the donor or have normal growth parameters due to the excess blood volume. However, as the condition progresses, volume overload can cause tissue edema and hydrops fetalis, marked by fluid accumulation in fetal compartments like the pericardium, pleura, and ascites. Neurological risks arise from the hemodynamic instability in the recipient twin, potentially leading to brain injury patterns such as periventricular leukomalacia, which is associated with long-term neurodevelopmental impairments including cognitive and motor deficits.Donor Twin Features
The donor twin in twin-to-twin transfusion syndrome experiences chronic hypovolemia due to net blood loss through placental arteriovenous anastomoses, leading to reduced intravascular volume and impaired organ perfusion. This manifests primarily as oligohydramnios, with a maximum vertical amniotic fluid pocket less than 2 cm, which compresses the gestational sac and creates the characteristic "stuck twin" appearance on ultrasound imaging, where the fetus appears fixed against the uterine wall with limited mobility.[1] Growth restriction is a hallmark feature, often presenting as intrauterine growth restriction (IUGR) with estimated fetal weight below the 10th percentile for gestational age, resulting from diminished nutrient and oxygen supply secondary to hypovolemia. Doppler ultrasound commonly reveals abnormal umbilical artery waveforms in the donor twin, including absent or reversed end-diastolic flow in advanced stages, signifying severe placental vascular resistance and compromised blood flow. Additionally, the donor exhibits oliguria due to renal hypoperfusion, which activates the renin-angiotensin-aldosterone system and leads to a collapsed, non-visible fetal bladder on sonography in stage II disease.[1] Hematological abnormalities include anemia, identifiable prenatally through elevated peak systolic velocity in the middle cerebral artery on Doppler assessment, reflecting compensatory increased cardiac output to maintain brain oxygenation. This hypovolemic state heightens the risk of multi-organ hypoperfusion, potentially affecting cardiac, renal, and cerebral function, though the donor twin may demonstrate vascular adaptations such as medial hypertrophy in placental vessels.[1]Maternal Symptoms
Mothers affected by twin-to-twin transfusion syndrome (TTTS) commonly experience symptoms arising from polyhydramnios in the recipient twin's amniotic sac, a consequence of unbalanced blood flow between the monochorionic twins.[12] This excess amniotic fluid causes abdominal distension, discomfort, and a sensation of tightness due to rapid uterine enlargement and pressure on surrounding organs.[13][14] In surveys of women with TTTS, sudden weight gain affected 76.2% of respondents, swelling occurred in 58.8%, and abdominal pain in 58.2%, with symptoms typically onsetting around 18 weeks gestation.[15] Uterine overdistension from polyhydramnios heightens the risk of preterm labor, manifesting as irregular contractions in 24% of cases and potential cervical shortening or effacement.[15][13] Monitoring uterine activity and cervical length is crucial, as these changes can precipitate premature delivery if unmanaged.[16] Severe polyhydramnios may also elevate the diaphragm, restricting lung expansion and leading to maternal respiratory distress or shortness of breath.[13] In rare instances, TTTS can produce systemic effects resembling preeclampsia, such as hypertension, generalized edema, sudden weight gain, and proteinuria, stemming from the maternal physiological response to fetal imbalances.[17]Diagnosis
Ultrasound Criteria
Diagnosis of twin-to-twin transfusion syndrome (TTTS) relies primarily on ultrasound imaging in monochorionic diamniotic twin pregnancies, with routine screening recommended to detect early signs of the condition.[18] For uncomplicated monochorionic twins, ultrasound surveillance begins at 16 weeks' gestation and is performed biweekly thereafter to assess for amniotic fluid discordance, fetal growth, and other indicators of imbalance.[1] This schedule allows for timely identification of TTTS, which typically manifests between 16 and 26 weeks.[18] The cornerstone ultrasound criteria for suspecting TTTS involve the oligohydramnios-polyhydramnios sequence, characterized by a maximum vertical amniotic fluid pocket of less than 2 cm in the donor twin's sac and greater than or equal to 8 cm in the recipient twin's sac.[19][10] Additional supportive findings include discordant fetal bladder filling, with the donor twin often showing a collapsed or non-visualized bladder due to oliguria, while the recipient exhibits a distended bladder from polyuria.[1] Growth discordance, defined as a difference in estimated fetal weight exceeding 20-25%, further supports the diagnosis when combined with fluid imbalances.[20] Doppler ultrasound enhances diagnostic accuracy by evaluating vascular hemodynamics. In the donor twin, absent or reversed end-diastolic flow in the umbilical artery indicates increased placental resistance and hypovolemia.[19] Elevated peak systolic velocity in the middle cerebral artery of the donor twin, typically greater than 1.5 multiples of the median, suggests fetal anemia resulting from chronic blood loss to the recipient.[1] In cases where ultrasound findings are equivocal or additional assessment is needed, complementary modalities may be employed. Magnetic resonance imaging (MRI) can provide detailed placental mapping and evaluation of fetal brain or organ volumes, particularly in advanced disease.[18] Fetal echocardiography is useful for detecting cardiac dysfunction in the recipient twin, such as tricuspid regurgitation or cardiomyopathy, which may accompany volume overload.[1] These criteria align with the Quintero staging framework for classifying TTTS severity but are primarily used for initial confirmation.[18]Quintero Staging System
The Quintero Staging System is a widely adopted classification for twin-to-twin transfusion syndrome (TTTS), developed to standardize assessment of disease severity based on ultrasound and Doppler findings, facilitating comparison of outcomes across treatment modalities.[21] Introduced in 1999, it categorizes TTTS into five progressive stages (I to V), reflecting escalating hemodynamic compromise and fetal risk, with staging performed through serial evaluations typically between 18 and 26 weeks of gestation to monitor progression.[1][21] A 2025 international consensus update proposes refinements, including a pre-TTTS stage for early detection, differentiation of donor and recipient disease in Stages III and IV, modified Stage III criteria incorporating critically abnormal fetal cardiovascular findings, and recognition of atypical TTTS with severe cardiac compromise without classic fluid discordance; however, the original Quintero system remains the primary framework in clinical practice pending further validation.[22] The system relies on key ultrasound criteria, including amniotic fluid discrepancies—oligohydramnios (deepest vertical pocket <2 cm) in the donor sac and polyhydramnios (≥8 cm) in the recipient sac—along with assessments of fetal bladder visibility and Doppler velocimetry of umbilical and ductal vessels.[1] Stages are defined as follows:| Stage | Criteria |
|---|---|
| I | Oligohydramnios/polyhydramnios sequence present; donor twin bladder visible; normal Doppler studies (umbilical artery, umbilical vein, ductus venosus).[1][21] |
| II | Oligohydramnios/polyhydramnios sequence present; donor twin bladder not visible; normal Doppler studies.[1][21] |
| III | Oligohydramnios/polyhydramnios sequence present; critically abnormal Doppler findings in either twin (e.g., absent or reversed end-diastolic flow in umbilical artery, pulsatile flow in umbilical vein, or reversed a-wave in ductus venosus).[1][21] |
| IV | Oligohydramnios/polyhydramnios sequence present; hydrops fetalis in one or both twins.[1][21] |
| V | Oligohydramnios/polyhydramnios sequence present; intrauterine demise of one or both twins.[1][21] |