Overview and Long-term Outcomes of Patients Born With Twin-to-Twin Transfusion Syndrome

Abstract

Twin-to-twin transfusion syndrome (TTTS) results from a disproportionate blood supply between two (or more) fetuses that share a single placenta. Multiple complications can occur as a result of the syndrome, including intrauterine growth restriction in the donor twin, cardiomyopathies in recipients, and neurodevelopmental morbidities in survivors. Studies indicate that patients with TTTS have higher incidences of congenital heart disease compared with the unaffected population, and even when compared with uncomplicated monochorionic diamniotic twins. If managed properly, TTTS can result in a positive outcome for most patients.

This article summarizes the available data for long-term outcomes of patients with twin-to-twin transfusion syndrome (TTTS). TTTS results from a disproportionate blood supply between two (or more) fetuses that share a single placenta. Transplacental communication was first documented in 1687, but it was not until 1941 that the coexistence of anemic and polycythemic twins was formally described as TTTS.¹

As knowledge of TTTS increased, its definition evolved as well. TTTS is diagnosed with ultrasound and the syndrome is defined as a monochorionic diamniotic pregnancy in which there is polyhydramnios (maximum vertical pocket of > 8 cm) in one amniotic sac and oligohydramnios (maximum vertical pocket of < 2 cm) in the other.² TTTS is a syndrome with a variable course and outcome. Therefore, in order to better quantify the severity of the disease in individual cases a staging system was proposed in 1990.²

In addition to the disparate volumes of amniotic fluid, staging is based on several other variables, including the appearance of the donor fetus’s bladder, abnormal umbilical blood flow as measured by Doppler ultrasound, the presence or absence of hydrops, and the death of one twin.² Using these variables, TTTS is staged from a score of I (mild) to V (severe).² The criteria for the Quintero staging system can be seen in Table 1. Several additional staging systems have since been developed in an attempt to better differentiate the nuances of TTTS, but the original Quintero staging system is still the most frequently used today.

Table 1.

Quintero Staging System

Stage	Polyhydramnios/Oligohydramnios	Visualization of Donor Bladder	Discrepancy of Umbilical Cords as Measured by Doppler	Fetal Hydrops	Fetal Demise
I	Yes	Yes	No	No	No
II	Yes	No	No	No	No
III	Yes	No	Yes	No	No
IV	Yes	No	Yes	Yes	No
V	Yes	No	Yes	Yes	Yes

TTTS has been estimated to affect 1 to 3 in 10,000 births.³ Although not included in the formal definition of TTTS, there are multiple complications that can occur as a result of the syndrome, including intrauterine growth restriction in the donor twin, cardiomyopathies in recipients, and neurodevelopmental morbidities in survivors.^4–6

Anatomy

An imbalance of blood flow from the placenta to the twin fetuses is primarily responsible for the difference in amniotic fluid levels that is the hallmark of TTTS. Aberrant placental morphology plays a large role in this disparity, with unidirectional arteriovenous anastomoses increasing the likelihood of TTTS.⁷ However, studies have also demonstrated that arterioarterial or venovenous anastomoses may serve a protective function.⁷ Rectification of discordant blood flow serves as the primary method of therapy in the majority of TTTS cases. It is important to note that although terms such as donor twin and recipient twin are used, there is evidence to suggest that there is not a direct shuttling of blood from one twin to the other in the majority of cases. In a study of 20 patients with TTTS, O-negative blood was transfused into the supposed donor twin, but was only detected in four of the recipient twins 24 hours later.⁸ Similar findings in other studies led to a shift away from the term TTTS to polyhydramnios-oligohydramnios sequence in the 1990s.

As it became apparent that blood flow discrepancies could not fully explain TTTS, researchers began to explore other possible etiologies for the disease.⁹ Additional research indicates involvement of the reninangiotensin system (RAS).⁹ Renin and angiotensin II have been demonstrated to be elevated in both donor and recipient, but research points to different mechanisms affecting this result in each twin. RAS is increased in the kidneys of donor twins, but down-regulated in recipients. The source of RAS components in the recipient twins is the placenta itself. This elevation in the donor twin is believed to be a result of hypovolemic status. This discrepancy has been hypothesized to play a role in the morphologic differences seen in TTTS.⁹

Management

Historically, there have been a variety of therapeutic options utilized in the treatment of TTTS. Options have ranged from conservative tactics, such as expectant therapy, to more aggressive approaches, including selective reduction and septostomy. These treatment modalities have since fallen out of favor and most physicians today offer one of two options: amnioreduction (AR), or fetoscopic laser surgery (FLS).

AR is performed by draining fluid from the recipient’s fetus amniotic sac in an effort to reduce the maximum vertical pocket to a size of 5 to 6 cm.¹⁰ FLS functions to photocoagulate the anastomoses within the placenta, thereby separating the circulation system of the twins.¹⁰ By separating the blood flow to the twins, the volume status of both normalizes. Due to decreased mortality and morbidity, FLS is the first-line treatment for most cases of TTTS.¹⁰ AR continues to play a role in treatment of patients with a gestational age < 26 weeks, mild disease, or in cases in which FLS was unsuccessful.¹¹ In rare cases, selective feticide remains an option. This option is generally reserved for cases in which a fetus suffers from severe placental insufficiency or when one twin demonstrates severe developmental abnormalities or brain injury.¹² It is important to emphasize that, to date, only three randomized controlled trials have undertaken to evaluate treatment modalities of TTTS, and all three were concluded earlier than anticipated. These trials demonstrated no significant difference in survival between septostomy and AR, and a significant increase in survival with FLS therapy compared with AR.^10,13,14 Survival statistics from these three randomized controlled trials are summarized in Table 2.

Table 2.

Survival Statistics for Various Treatment Modalities of Twin-to-Twin Transfusion Syndrome

	Survival of ≥ 1 Infant (%)	Survival of ≥ 1 Infant: Quintero Stage III, IV (%)	Overall Survival (%)
Septostomy	28/35 (80)	—	49/70 (70)
Amnioreduction	28/36 (78)	15/34 (44)	46/72 (64)
	15/20 (75)		24/40 (60)
	36/70 (51)		54/140 (38.5)
Fetoscopic laser surgery	18/40 (45)	23/35 (66)	18/40 (45)
	55/72 (76)		81/144 (52)

Data from Senat MV et al,¹⁰ Moise KJ Jr et al,¹³ and Crombleholme TM et al.¹⁴

Neurologic Effects and Outcomes

Necrosis of cerebral white matter occurs more often in monochorionic twins, and multiple vascular connections within the placenta is the most strongly associated risk factor.¹⁵ Despite this knowledge, the pathogenesis of cerebral damage in TTTS remains poorly understood.¹⁶ Proposed theories suggest that hemodynamic disturbances result in hemorrhagic brain lesions and ischemia, leading to cerebral morbidity.¹⁷ Other sources of injury in the postnatal period resulting from low birth weight and prematurity likely play a role as well.¹⁵

The decrease in neurologic sequelae in patients receiving FLS treatment when compared with AR supports the idea of hemodynamic influences on neurologic outcomes. A threefold increase in severe cerebral injury occurs in surviving neonates treated with AR instead of FLS.¹⁸ AR-treated individuals also have higher odds of periventricular leukomalacia and intraventricular hemorrhage in the neonatal period; importantly, there remains some ambiguity into the degree of risk.^10,18 The risk of neurodevelopmental delay at 2 years of age is elevated for those who undergo AR therapy.¹⁷ Children treated with FLS score statistically better on fine motor and social skill tests, and trends point toward better overall neurologic development and decreased abnormalities at 2 years of age.¹⁷

Neurodevelopmental outcomes of TTTS patients who underwent FLS do not vary significantly from 2 years and 10 months of age to 6 years and 5 months of age.¹⁹ In a study of 160 individuals aged 6 years, 11.6% of children struggled with mild neurologic impairment and 8.9% suffered from severe neurologic impairment.¹⁹ Examples of mild neurologic impairment included language delay and strabismus, whereas cerebral palsy and mental retardation were considered severe neurologic impairment. ¹⁹ Unlike cardiac outcomes, neurologic outcomes did not differ between recipients and donors.¹⁹

Despite these differences in outcomes based on the treatment therapy used, the most important predictor of neurodevelopment impairment is gestational age. One study demonstrated 100% of patients born before 28 weeks experienced major neurologic sequelae despite FLS. Conversely, no major sequelae occurred in cases of gestational age > 32 weeks.²⁰ Additional studies suggest using a routine cranial ultrasound after birth in TTTS patients as a means of predicting long-term neurodevelopmental outcomes, although the effectiveness of ultrasound as a screening tool is yet to be seen.²¹

Cardiologic Effects and Outcomes

Multiple studies indicate that patients with TTTS have higher incidences of congenital heart disease compared with the unaffected population, and even when compared with uncomplicated monochorionic diamniotic twins.^4,12,22 Due to their hypervolemic status, recipient twins demonstrate multiple cardiac abnormalities, the most prevalent of which include cardiomegaly, biventricular hypertrophy, and atrioventricular valve regurgitation. ²³ Despite their volume-depleted status, the donors in TTTS demonstrate minimal cardiac pathology, with the exception of increased afterload resulting from the aberrant placental architecture. ²³ Heart disease is a major cause of death in those with TTTS, causing half of the deaths that occur in the postnatal period in TTTS recipients.¹² Fetal heart failure resulting in recipient death is 2.7 times more likely in cases in which AR is performed instead of FLS.¹² This is likely because FLS effectively halts the progression of cardiac disease by obliterating placental anastomoses, whereas the unequal hematologic distributions are unaffected by AR therapy.¹² For patients who survive the neonatal period, 87% demonstrate normal cardiac examination results.²³

In a study of 89 survivors of severe TTTS treated with FLS, ventricular function normalized by 15 months of age. Despite such an improvement, these patients with TTTS are at risk for long-term cardiac disease, as the incidence of congenital heart disease was increased compared with the general population.²³ Although the exact mechanism of congenital heart disease in TTTS remains to be determined, some patterns point to a cause. Pulmonary stenosis occurred only in recipients in the study and occurred at a greater rate than the general population (4.5% vs 0.038%).²³ This increased risk of pulmonary stenosis likely stems from the volume overload status of the right ventricle prior to successful FLS.²³

The prevalence of atrial septal defects, which were found in recipients and donors, was elevated as well when compared with the general population.²³ Mediumsized atrial septal defects had a statistically significant elevated frequency.¹² Despite the increased risk of congenital heart disease in those with TTTS, the elimination of diastolic and systolic dysfunction with a resulting normalization of cardiac function would seem to indicate high plasticity of a pediatric heart once the stressor has been removed.²³ As expected, however, this plasticity is unable to overcome the congenital developmental defects that ensue from TTTS. A summation of neonatal and longterm sequelae from TTTS is found in Table 3.

Table 3.

Organ System Abnormalities Resulting from Twin-to-Twin Transfusion Syndrome

Potential Organ System Abnormalities	Neonatal Period	Long Term
Neurologic	Periventricular leukomalacia, intraventricular hemorrhage	Language delay, strabismus, mental retardation, cerebral palsy
Cardiogenic	Cardiomyopathy with systolic or diastolic dysfunction	Pulmonary stenosis, atrial septal defect
Other	Anemia/polycythemia, limb ischemia	Unknown

Counseling

FLS remains the first-line treatment in patients with TTTS due to its markedly improved morbidity and mortality outcomes when compared with AR. Despite the effectiveness of FLS, physicians should have a realistic conversation with parents regarding its limitations. Even for patients with limited disease, the survival rate for both twins at 6 months of age is approximately 86%.¹⁰ Furthermore, parents must be aware of other procedural concerns, such as the invasiveness of the procedure and the continued need for long-term follow-up, even if the procedure proves successful. ^10,12 As noted, several other therapeutic options, including AR, are also available. The spectrum of treatment options must be made available so that parents can make an informed decision regarding how to proceed.

The neurologic outcome of their children is of paramount concern to parents. Approximately 20% of children surviving the neonatal period with TTTS will have some form of neurologic impairment.^17,19 Although most of these cases are relatively mild, the fact that they persist up to a minimum of 6 years of age suggests some form of permanent mental delay. Although it is tempting because the majority of children have normal mental development, physicians should not understate the increased risk of disease.

It is important to make sure parents are aware that possible cardiac dysfunction can occur even in the early stages of TTTS. The most common staging systems used by physicians to relay to parents the severity of disease often fail to fully evaluate the cardiovascular manifestations of disease.¹² Based on the results of the current data, the evidence suggests that if patients navigate the initial neonatal period successfully, there is a high likelihood that they will develop with normal cardiac function. As noted previously, the high prevalence of positive outcomes is probably due to the plasticity of pediatric cardiac tissue and its ability to recover upon the removal of physiologic stressors.

When having conversations with parents regarding the expected outcomes of TTTS, physicians must to take into account the large variance that can be seen in the disease and tailor conversations to the specific case at hand. Although physicians and care providers can expound on the current research and their own judgment, sometimes patients require more assistance. There are multiple support groups available for parents of children with TTTS, and physicians should provide group information and encourage involvement in those groups.

Conclusions

TTTS is a rare disorder that, if properly managed, results in a positive outcome of the pregnancy for most patients. Due to the low rate of incidence of this disease and its unique physiology, most expectant parents are unaware as to disease progression and outcomes. Traditionally, physicians had to rely on the few studies that were available, in addition to their own clinical judgment. Today, the long-term outcome of patients who have TTTS during gestation is an area of increasing interest and research. Focus has revolved around neurologic and cardiologic outcomes and the differences in occurrence rates when patients are treated with AR or FLS. Ideally, future studies will examine long-term renal function due to the role RAS plays in the pathogenesis of TTTS. As research into TTTS continues to grow at an accelerating pace, it is exciting to consider the possibilities for improved patient care and outcomes that will soon be available.

Main Points.

• Twin-to-twin transfusion syndrome (TTTS) results from disproportionate blood supply between two (or more) fetuses that share a single placenta. It is defined as a monochorionic diamniotic pregnancy in which there is polyhydramnios in one amniotic sac and oligohydramnios in the other.

• Most physicians today offer one of two treatment options, amnioreduction (AR), or fetoscopic laser surgery (FLS). AR is performed by draining fluid from the recipient’s fetus amniotic sac in an effort to reduce the maximum vertical pocket. FLS functions to photocoagulate the anastomoses within the placenta, thereby separating the circulation system of the twins. By separating the blood flow to the twins, the volume status of both normalizes. FLS is the first-line treatment for most cases of TTTS.

• The decrease in neurologic sequelae in patients receiving FLS treatment when compared with AR supports the idea of hemodynamic influences on neurologic outcomes. A threefold increase in severe cerebral injury occurs in surviving neonates treated with AR instead of FLS.

• Multiple studies indicate that patients with TTTS have higher incidences of congenital heart disease compared with the unaffected population, and even when compared with uncomplicated monochorionic diamniotic twins.