Twin-Twin Transfusion Syndrome

TTTS occurs in approximately 10% of monochorionic twins. Most experts believe that TTTS develops in monochorionic twin pairs as a result of unbalanced net flow of blood through vascular communications in the shared placenta. A series of pathophysiologic changes ensue from the net shunting of blood from one twin (donor) to the other twin (recipient), resulting in hypovolemia and oliguria in one, and volume overload and polyuria in the other ( Fig. 24-4A ). These hemodynamic derangements result in a cascade of physiologic changes leading to donor twin oligohydramnios, recipient twin polyhydramnios, and characteristic anatomic and arteriovenous flow alterations that can be identified by sonography with Doppler. Without intervention, early severe TTTS has a very high rate of perinatal injury or death.

A, Monochorionic twin placenta, demonstrating arteriovenous vascular (A → V) connection. B, Diagram illustrating sonographic guidance for laser ablation for twin-twin transfusion syndrome. Doppler interrogation is used to identify arterial and venous connections, and laser energy is applied to the site of anastomosis.

The diagnosis of TTTS is based on the following in utero ultrasound-based criteria: (1) monochorionicity and (2) single maximal vertical pocket (MVP) of amniotic fluid less than 2.0 cm on one side of the dividing membrane, and MVP of more than 8.0 cm on the other side. Once the diagnosis has been established, the syndrome may be staged according to the Quintero staging system ( Table 24-2 ). The establishment of diagnostic criteria and the classification of TTTS by Quintero and associates. have allowed researchers to compare outcome data following various therapeutic interventions and to predict perinatal survival after treatment.

The perinatal mortality rate of expectantly managed TTTS has been reported to be as high as 95%. Of the various treatment approaches that have been considered for TTTS, those with the best-reported outcomes are serial amniocenteses and selective laser photocoagulation of communicating vessels (SLPCV) via operative fetoscopy ( Fig. 24-4B ). Serial amniocentesis (or amnioreduction) involves drainage of amniotic fluid from the polyhydramniotic recipient sac using vacuum-assisted devices attached to an 18- to 20-gauge spinal needle. The volume of amniotic fluid that should be withdrawn has not been standardized, although usually the MVP of amniotic fluid in the recipient sac is reduced to approximately 8 cm or less. Serial amniocenteses serve to significantly reduce the amount of amniotic fluid in the recipient sac, thereby diminishing overall uterine distention.

SLPCV is performed via operative fetoscopy, allowing direct visualization of the vessels on the placental surface. Once mapping of vascular communications has been performed, those vessels are occluded using laser energy ( Figs. 24-5 and 24-6 ). The basic principle of SLPCV is that the causative inter-twin vascular communications are ablated, thus treating the underlying pathogenic cause of this syndrome. With laser surgery, the circulations in a shared placenta are divided, functionally converting it to a dichorionic twin pregnancy, with improved perinatal outcomes.

Laser for twin-twin transfusion syndrome. Fetoscope can be seen adjacent to twin A in the polyhydramniotic sac. The placenta is posterior.

Fetoscopic image of the fetal surface of a monochorionic twin placenta in the region of the vascular equator. Two placental arteries (a) from the donor twin communicate with placental veins (v) of the recipient twin, shown before ( A ) and after ( B ) laser photocoagulation.

After the introduction of laser ablation as a treatment option for TTTS, the Eurofetus group conducted a randomized controlled trial that compared serial amniocentesis to SLPCV. Pretrial power analysis projected the need for a total of 172 patients to demonstrate a significant difference in outcomes between the two treatment arms. However, after enrollment of 142 patients, interim analysis revealed that the perinatal survival rate of at least one twin was 51% (36/70) in the amnioreduction arm versus 76% (55/72) in the laser therapy arm. Based on this statistically significant difference, the study was halted. In addition, in the laser group, pregnancy duration was approximately 4 weeks longer (33 weeks vs. 29 weeks, P = 0.003). The amnioreduction group had a significantly higher rate of neurologic complications (14% vs. 6%, P = 0.02), and this difference persisted at the 6-month follow-up evaluation.

Most subsequent studies have confirmed that SLPCV is the optimal treatment for TTTS. Intervention with laser surgery has resulted in survival rates for at least one twin ranging from 65% to 93% and dual survival rates ranging from 18% to 62%. Although several factors may influence perinatal outcomes in laser-treated TTTS patients, one important consideration is disease severity. Knowledge of perinatal outcomes of TTTS pregnancies treated with laser, stratified by Quintero stage, may facilitate patient selection and counseling. In a series of 682 consecutive cases of TTTS treated via SLPCV, there was a 91% perinatal survival rate of at least one twin and 67% survival rate of both twins. Of note, perinatal survival of at least one fetus has been reported to be independent of Quintero stage, whereas dual twin survival does appear to differ based on stage. This is predominantly because stage III pregnancies are associated with decreased donor twin survival ( Table 24-3 ), particularly in those with growth restriction of the donor. These pregnancies are nearly twice as likely as those without growth restriction to suffer in utero demise of the donor. The average gestational age at delivery following laser surgery is approximately 33 weeks, with 10% delivering between 24 and 28 weeks’ gestation. The laser surgical technique has undergone recent modifications that may further improve perinatal outcomes.

The surgical goal of SLPCV is to completely occlude all placental vascular connections between the twin pair. A missed or inadequately lasered vessel, referred to as a residual anastomosis (RA), may be associated with adverse perinatal outcomes such as persistent or reversed TTTS or TAPS. Pathologic confirmation of complete ablation of vascular communications can be ascertained via ex vivo placental injection studies in cases without placental maceration related to IUFD. RA after SLPCV has been reported to be as low as 4% to 5%, although some studies have reported frequencies of RA ranging from 32% to as high as 75% of cases. In a 2014 trial investigating laser coagulation of the entire vascular equator, the rate of RA was still 19%. The wide range of RA rates in these studies has been attributed to the laser technique employed and to the method of placental evaluation.

Despite evidence that SLPCV improves neonatal survival and reduces morbidity, cerebral injury is not fully prevented. Periventricular infarction, hemorrhagic injury, and ischemic white matter damage have been detected prenatally in fetuses treated with laser surgery for TTTS. The incidence of cerebral damage may be underestimated, because neurodevelopmental impairment and intellectual disability may only manifest several months or years after birth. Thus, a major concern for clinicians and parents is the rate of neurologic impairment in survivors. A systematic review found that the risk of neurodevelopmental impairment after laser therapy for TTTS is about 11%. Cerebral palsy was the most frequent diagnosis, accounting for about 40% of abnormal neurologic outcomes. In a cohort of 100 TTTS survivors treated with in utero laser surgery, formal neurodevelopmental testing, performed at 2 years of age, revealed normal range mean Battelle Developmental Inventory, 2nd edition (BDI-2) scores of 101.3 (standard deviation [SD] = 12.2) for the entire cohort. The overall rate of neurodevelopmental impairment, defined as blindness, deafness, cerebral palsy, or BDI-2 score less than 70, was 4%.

Selective Fetal Growth Restriction

sFGR, defined as one twin with an estimated fetal weight (EFW) below the 10th percentile for gestational age, is reported to occur in at least 10% of monochorionic twin pairs. It is important to note that significant growth discordance with or without amniotic fluid discordance is not required for the diagnosis of sFGR. sFGR appears to be distinct from TTTS, although there may be significant overlap in these conditions. It is believed that sFGR develops because of unequal placental share, with the sFGR fetus perfusing a smaller portion of the single shared placenta.

Although disproportion in placental territories allocated to monochorionic twin pairs appears to be the primary contributor to sFGR, the presence of vascular communications plays an important role in perinatal outcome. There is increased likelihood of spontaneous in utero demise of the sFGR fetus, which may result in concomitant demise or severe neurologic handicap of the co-twin. Following demise of the sFGR twin, sudden redistribution of blood flow via placental vascular connections can lead to acute hypotension in the surviving co-twin. Thus, the larger (appropriately grown for gestational age, AGA) twin may face an increased risk of neurodevelopmental impairment related to co-twin demise or prematurity. One observational study monitored 84 consecutive monochorionic twin pairs with discordant amniotic fluid that did not meet criteria for TTTS and showed a 60% (23/38 fetuses) overall survival rate in the subgroup that met criteria for sFGR. In another study of 17 pregnancies with sFGR that were managed expectantly, the survival rate of the sFGR twin was 59%. The rate of short-term intracranial injury (including periventricular leukomalacia, intraventricular hemorrhage, and ventriculomegaly) in this group of patients was 14%. In a separate review, the overall incidence of severe cerebral injury in survivors of pregnancies complicated by sFGR was found to be approximately 8%. Factors associated with poor neurologic outcomes included abnormal umbilical artery Doppler waveforms, intrauterine co-twin demise, and earlier gestational age at birth.

The understanding of the pathophysiologic changes of sFGR has advanced significantly in recent years. A staging system based on umbilical artery Doppler findings was proposed by Gratacos and colleagues in 2007 and is now used by some centers. The authors classified monochorionic twin pregnancies complicated by sFGR into three categories based on umbilical artery Doppler waveforms of the sFGR twin, as follows: type I with persistent forward diastolic flow; type II with persistent absent or reversed end-diastolic flow (AREDF); and type III with intermittent absent or reversed end-diastolic flow (iAREDF). These three groups are associated with different patterns of placental anastomoses and with different clinical courses, which can influence prenatal monitoring and management.

In type I sFGR, the median age at diagnosis is approximately 20 weeks’ gestation. In utero deterioration is not common in this group. Once this diagnosis is made, umbilical artery Doppler findings in the sFGR twin usually remain normal until delivery. It is reasonable to maintain close surveillance with weekly sonograms with Doppler, and to escalate follow-up as necessary. There appears to be no benefit from fetal intervention in this group, and it is reasonable to plan delivery at 34 to 35 weeks’ gestation in the absence of obstetric indications for earlier delivery.

At this time, the optimal treatment strategy for monochorionic twin pregnancies complicated by sFGR type II, with persistent AREDF in the umbilical artery, is not clear. Expectant management requires close monitoring of the pregnancy with sonography or fetal heart rate monitoring, often in the hospital setting, from 24 weeks’ gestation until delivery, aiming to prolong the pregnancy yet intending to deliver the twins prior to demise of the growth-restricted fetus. The umbilical artery Doppler findings cannot be used to predict imminent fetal demise. Doppler interrogation of the ductus venosus (DV) appears to be the best adjunct for fetal surveillance, as is done in singleton pregnancies complicated by FGR. Observation of absent or reversed a-wave flow on DV waveforms should prompt the clinician to consider delivery or fetal intervention, depending on gestational age. If the DV waveform remains normal, the patient can be followed once or twice a week. Expectant management is associated with a very high (nearly 100%) rate of prematurity, with risk of neurologic injury to the AGA twin. Intervention may be considered in cases of type II sFGR, particularly when the diagnosis is made prior to viability. One therapeutic option is to perform operative fetoscopic ablation of all inter-twin vascular communications, thereby creating a “functionally” dichorionic twin gestation. The surgical intervention is similar to the laser technique used for treatment of TTTS, although the procedure may be technically more difficult. Quintero and coworkers performed a feasibility study that showed a trend toward decreased rate of neurologic deficits in the AGA twin (14% rate of neurologic injury in the expectantly managed group versus 0% in the SLPCV group). Chalouhi and associates found that SLPCV resulted in a survival rate of 52% in sFGR twins and 74% in AGA twins. As an alternative to fetoscopic SLPCV, umbilical cord occlusion (UCO) or radiofrequency ablation (RFA) of the sFGR twin has been offered. These techniques aim to protect the AGA twin from potential injury or death resulting from spontaneous in utero demise of the sFGR co-twin. These approaches, by definition, result in demise of the sFGR fetus. Selective reduction in these circumstances has resulted in survival rates of the AGA co-twin of 74%.

Type III sFGR is characterized by iAREDF in the umbilical artery of the sFGR twin. The umbilical artery Doppler waveform pattern displays cyclic changes during diastole, such that there is alternating positive AREDF. This unique Doppler waveform suggests the presence of a large arterioarterial (AA) anastomosis within the shared placenta, coursing between the twins’ cord insertion sites. Outcomes of pregnancies with evidence of type III sFGR may be difficult to predict. Unexpected IUFD has been reported in approximately 15% of cases, with sudden death documented hours after a normal Doppler ultrasound examination. Another study has reported that the AGA twin has an elevated risk of postnatal white matter lesions, even if the smaller twin is born alive. Thus, management of these pregnancies is challenging. Fetoscopic laser ablation of vascular connections has been attempted in this population, but the results were not favorable compared to expectant management. SLPCV could not be completed in over 10% of cases owing to technical difficulties, and overall perinatal survival rate was 64% in the laser group compared to 86% in those managed expectantly. However, it should be noted that the prevalence of leukomalacia in the larger infant was 1/17 (5.9%) in the laser group versus 4/28 (14.3%) in the expectantly managed group.

Late-onset sFGR, referring to the development of growth restriction of one twin after 26 weeks’ gestation, is another previously described subgroup of complicated monochorionic twin gestations. The prevalence of late-onset sFGR among monochorionic twin pairs has been reported by Lewi and colleagues to be 6.3% in a cohort of 208 pregnancies. Mean gestational age at delivery was 35 weeks and 38% of infants met postnatal diagnostic criteria for TAPS. There was one intrauterine death.

Twin Anemia-Polycythemia Sequence

TAPS is an atypical form of TTTS that also appears to be caused by a net transfer of blood from one monochorionic twin to the other. TAPS is characterized by large inter-twin hemoglobin differences in the absence of oligohydramnios and polyhydramnios. This condition may develop spontaneously (2-6% of monochorionic twins) or as a result of residual vascular communications following laser surgery (2-13% of monochorionic twins who have had laser). Unlike TTTS, which is likely due to more acute hemodynamic imbalances, the pathogenesis of TAPS has been attributed to chronic net transfusion from one twin to the other, presumably at a slow enough rate to allow for hemodynamic equilibration. TAPS may result in severe anemia in one twin and polycythemia in the other ( Fig. 24-7 ). Placental pathologic studies have shown that pregnancies complicated by TAPS have relatively few, small-caliber (<1 mm) arteriovenous communications as compared to larger arteriovenous communications seen in placentas from pregnancies affected by classic TTTS.

Fetoscopic image demonstrating striking discordance in coloration between monochorionic twin fetuses with TAPS (twin anemia polycythemia syndrome). The red foot belongs to the polycythemic (p) twin and the pale white foot belongs to the anemic (a) twin.

Although there is not consensus in the literature, the antenatal definition of TAPS usually requires that the middle cerebral artery (MCA) peak systolic velocity (PSV) measures greater than 1.5 multiples of the median (MoM) in the anemic twin and less than 1.0 MoM in the polycythemic twin, and that the pregnancy is not affected by oligohydramnios or polyhydramnios. An antenatal staging system has been proposed, and although it has not been validated clinically, it is useful to facilitate communication between practitioners. Stage 1 is defined as MCA PSV measurement greater than 1.5 MoM in one twin and less than 1.0 MoM in the other, without evidence of fetal compromise. Stage 2 is defined as MCA PSV greater than 1.7 MoM in one twin and less than 0.8 MoM in the other, also without signs of fetal compromise. Stage 3 requires fulfillment of stage 1 or 2 criteria, with additional finding of critically abnormal Doppler waveforms (defined as AREDF in the umbilical artery, pulsatile flow in the umbilical vein, or reversed a-wave flow in the DV) in the anemic twin. Stage 4 includes hydropic changes in the anemic twin, whereas stage 5 is defined as demise, preceded by TAPS, of one or both twins. Postnatal diagnostic criteria and classification, described by the same investigators, requires an inter-twin hemoglobin difference of more than 8 g/dL and at least one of the following: reticulocyte count ratio more than 1.7 and placental pathologic findings of only small (<1 mm diameter) inter-twin vascular communications.

Given the relatively low prevalence and lack of clinical awareness of this condition, the natural history of TAPS is unclear and decision making regarding antenatal treatment is controversial. Case series have reported expectant management with timed delivery, intrauterine fetal transfusion, and fetoscopic laser treatment. Favorable outcomes have been described in pregnancies with uncomplicated TAPS using expectant management or other conservative measures, particularly in those diagnosed in the third trimester. Spontaneous resolution of TAPS has also been reported. However, TAPS may progress and result in perinatal death or neurologic injury. Polycythemia can lead to vascular sludging, which may lead to cerebral venous thrombosis resulting in intraventricular hemorrhage and parenchymal infarction, and fetal anemia may affect cerebral oxygenation resulting in hypoxic-ischemic cerebral injury. Timed delivery, on the other hand, must be weighed against the risks of prematurity. Although survival rates of 75% can be obtained with expectant management, it has been suggested that treatment with IUT or laser surgery can increase survival to over 90%. A recent 2014 study has reported that neurodevelopmental impairment and cognitive delay were found in almost 20% of children surviving posttreatment for TAPS, with the lowest cognitive scores detected in the subgroup of TAPS survivors treated with IUT. It is not known whether survivors of spontaneously resolved TAPS face a similar risk for neurodevelopmental impairment or cognitive delay.

IUT has been suggested as a temporizing, symptomatic treatment of the anemic twin in a pair affected by TAPS. However, there is concern that transfused blood may worsen symptoms in the recipient (polycythemic) twin, which might then develop iatrogenic complications related to hyperviscosity, such as limb necrosis. Two cases have exhibited spontaneous placental vascular thromboses, possibly because of hyperviscosity in the polycythemic twin. Thus, IUT (without definitive laser surgery) may exacerbate the risk of vascular thromboses and other complications. The use of intrauterine partial exchange transfusion may help reduce the risk of severe polycythemia complications. On the other hand, partial exchange transfusion in the neonate has been associated with suboptimal coagulation with subsequent disseminated intravascular coagulation, so this procedure is not without risk.

Fetoscopic laser surgery is the only definitive treatment for TAPS. Laser surgery may be beneficial in pregnancies complicated by TAPS, particularly in high-risk cases in which additional ultrasound findings suggest fetal compromise. However, laser surgery may be technically more challenging in TAPS than in TTTS given the absence of polyhydramnios, absence of a “stuck” twin, slack inter-twin membrane, and difficulty visualizing the very small communicating vessels. Nevertheless, reports of fetoscopic laser treatment for TAPS have indicated that this intervention can be effective. Further research is needed to establish selection criteria for in utero treatment of TAPS, possibly based on the presence of coexisting amniotic fluid discordance; Doppler waveform abnormalities in the umbilical artery, umbilical vein, or DV; sFGR; hydrops fetalis; cervical insufficiency; or gestational age at onset.

Twin Reversed Arterial Perfusion Sequence

TRAP sequence affects approximately 1% of monochorionic twins, or about 1 in 35,000 pregnancies. The presence of direct artery-to-artery and vein-to-vein placental anastomoses allows one fetus (pump twin) to perfuse the other anomalous fetus, typically referred to as an acardiac fetus (perfused twin). The term acardiac fetus is at times a misnomer, as the perfused twin may rarely have a rudimentary heart. The perfused twin is supplied with blood flowing in a reversed direction (the umbilical artery delivers blood to the perfused twin and the umbilical vein carries blood away, toward the placenta). Because of the direct artery-to-artery anastomosis, the deoxygenated blood from the pump twin is carried to the perfused twin through that twin’s umbilical artery or arteries. The perfused twin, typically with no functional beating heart, has severe maldevelopment of cephalic, thoracic, and upper extremity structures, which is not compatible with postnatal survival.

Ultrasound diagnosis of TRAP sequence can be made in the first and early second trimesters, particularly with the aid of color and spectral Doppler techniques. Note that the lack of a beating heart within the perfused twin may be misinterpreted as co-twin demise. In some cases, the presence of a rudimentary heart may be confusing. In this setting, it is important to interrogate the cord insertion site at the anterior abdominal wall of the anomalous fetus to assess for reversal of flow direction in the umbilical artery ( Fig. 24-8 ).

Twin reversed arterial perfusion (TRAP) sequence. Transaxial ultrasound image of the acardiac twin at the level of the umbilical cord insertion. Color and spectral Doppler interrogation demonstrates reversed pulsatile arterial flow (in blue ), directed away from the transducer toward the acardiac fetus. This Doppler ultrasound finding is pathognomonic of TRAP sequence.

The risk of pump twin demise is as high as 50% to 75% due to the hemodynamic burden and volume overload. Risk factors for poor perinatal outcome include polyhydramnios in the pump twin, critically abnormal Doppler waveforms, hydrops, or a large perfused anomalous twin measuring greater than 50% of the pump twin’s estimated weight. If at least one of these factors is present between 16 and 26 weeks’ gestation, the patient should be offered the option of intervention to achieve UCO of the perfused twin. In one study of 74 cases complicated by TRAP sequence, high-risk factors were defined as at least one of the following ultrasound findings: (1) abdominal circumference of the perfused twin equal to or greater than that of the pump twin, (2) polyhydramnios (maximum vertical pocket > 8 cm), (3) abnormal Doppler waveform in the pump twin, (4) hydrops of the pump twin, or (5) monoamniotic twins. The perinatal survival rate for the high-risk pump twins in those patients who did not elect to undergo UCO was 43%. Current reported perinatal survival rates of high risk pump twins who have undergone UCO is approximately 80% to 90%.

A variety of techniques have been used to achieve UCO of the acardiac twin. Fetoscopic UCO is one common approach, and can be performed using a variety of surgical techniques, such as umbilical cord laser photocoagulation, laser of the placental vascular communications, and suture ligation. Similar results can be achieved with bipolar electrocautery and intrafetal RFA ( Fig. 24-9 ). Each approach is particularly suited to a given clinical circumstance, and the UCO modality is usually dictated by technical considerations, availability of instrumentation, and surgeon preference.

Radiofrequency ablation of acardiac fetus. A, Device is deployed into fetal abdomen at level of cord insertion ( arrow ). B, Bright reflection from gas bubbles created during radiofrequency ablation procedure. C, Color Doppler confirms absent flow in acardiac fetus following procedure.

Twins With Discordant Structural Anomalies

Monochorionic twins may be affected by discordant structural anomalies. Patients with monochorionic twins discordant for a severe congenital anomaly, particularly those at significant risk of in utero demise, should be offered the option of selective reduction by UCO. Treatment via intravascular potassium chloride (KCl) injection is the primary method for selective reduction in dichorionic twins but is contraindicated in monochorionic twin gestations for two reasons. First, vascular communications within the monochorionic placenta may serve as a conduit for passage of the injected agent to the co-twin. Second, following reduction, acute exsanguination or hypotension of the co-twin via the connections in the shared placenta can result in neurologic injury or death. Thus, in these cases, UCO can be performed in a similar fashion to that described for TRAP sequence. As there are potential complications, including injury to the co-twin, those monochorionic twin pregnancies with discordant anomalies for whom UCO is considered require careful assessment and counseling of the risks and benefits particular for each case.