NORD gratefully acknowledges Mark P. Johnson, MD, Center for Fetal Diagnosis and Treatment, The Children's Hospital of Philadelphia, for assistance in the preparation of this report.
Twin-twin transfusion syndrome (TTTS) is a rare disorder that sometimes occurs when women are pregnant with identical (monozygotic) twins. It is a rare disease of the placenta, the organ that joins the mother to her offspring and provides nourishment to the developing fetuses. During the development of identical twins, there are always blood vessels in the fetuses' shared placenta that connect their blood circulations (placental anastomoses). In most cases, the blood flows properly through these vessels. However, in twin-twin transfusion syndrome, the blood begins to flow unevenly, with one fetal twin receiving too much blood (recipient) and one receiving too little (donor). The recipient twin may experience heart failure due to continual strain on its heart and blood vessels (cardiovascular system). The donor twin, on the other hand, may experience life-threatening anemia, insufficient nutrition and oxygen due to its inadequate supply of blood. Such an imbalance in blood flow (i.e., twin-twin transfusion) can occur at any time during the pregnancy, including during delivery.
The effects of twin-twin transfusion syndrome can vary in severity from case to case, depending upon when during pregnancy the syndrome occurs, when it is diagnosed, and any treatment that may be given. The cause of this syndrome is not fully understood, although it is known that placental characteristics play an important role.
Twin-twin transfusion syndrome (TTTS) is a rare disorder that sometimes occurs when women are pregnant with identical (monozygotic) twins. TTTS is a disease of the placenta, the organ that develops in the uterus during pregnancy, links the mother’s blood supply to the fetuses’, and provides nourishment to her offspring. The developing fetal twins are typically normal until abnormalities in blood flow within the placenta cause the TTTS disease process to occur.
The majority of identical twins share a common placenta in which blood vessels connect the fetuses’ umbilical cords and blood circulations (placental anastomoses). The umbilical cords join the fetal twins to the placenta. In most cases, the blood flow is balanced between the twins through these connecting blood vessels. However, when twin-twin transfusion syndrome occurs, the blood begins to flow unevenly through the connecting blood vessels. As a result, one fetal twin receives too much blood (recipient), while the other receives too little (donor). The fetal twins, though developing normally up to this point, may now begin to exhibit various symptoms, depending upon when in the pregnancy the imbalance in blood flow (twin-twin transfusion) has taken place.
The twin-twin transfusion may occur at any time during pregnancy. If the imbalance in blood flow occurs early in the pregnancy (first trimester), one of the fetal twins may simply cease developing; as a result, only one fetus will be detected for the remainder of the pregnancy. If the transfusion occurs shortly before or during delivery, the twins may exhibit symptoms related to a sudden lack or excess of blood supply. However, should twin- twin transfusion syndrome occur during mid-pregnancy (second trimester), a variety of symptoms may occur.
For example, the twin that receives extra blood (recipient) begins to produce more urine than normal (polyuria), resulting in excessive amniotic fluid surrounding the fetus within its amniotic sac (hydramnios). Such an excess of amniotic fluid can develop quickly, often over two to three weeks As a result, the mother’s abdomen grows larger than normal for her stage of pregnancy. In most cases, this is the first symptom of twin-twin transfusion syndrome. Left untreated, the excess amniotic fluid can cause preterm labor or rupture the amniotic sac, resulting in potentially very early delivery.
On the other hand, because the other fetal twin (donor) receives too little blood and has abnormally low levels of circulating fluid in its body (hypovolemia), its kidneys may stop producing urine (renal shutdown); there may therefore be very little fluid in the donor twin’s amniotic sac (oligohydramnios). As a result, the sac’s membranes (amnion) may collapse around the fetus. Because this fetal twin may appear stuck or “cocooned” within the collapsed membranes, it is sometimes called the “stuck twin”.
During normal fetal development, most identical (monozygotic) twins grow at approximately the same rate and have similar weights when they are born. However, if fetal twins are affected by twin-twin transfusion syndrome by mid-pregnancy (second trimester), they may begin to vary greatly in development rate and size. While the recipient twin may become larger in size than normal, the donor twin may suffer from severe growth retardation.
Some researchers believe that uneven sharing of portions of the common, shared placenta may also contribute to different rates of growth. The difference in sizes of the twins may persist even after birth through infancy.
Both recipient and donor fetal twins may exhibit other symptoms as well. The extra blood supply to the recipient twin may cause heart failure resulting in fluid to accumulating in some of its body cavities (hydrops), such as in the abdominal cavity (ascites), around the lungs (pleural effusion), and/or around the heart (pericardial effusion). Receiving excess blood places continual strain on the fetus’s heart and blood vessels (cardiovascular system), which may eventually cause congestive heart failure. On the other hand, the donor twin has an inadequate supply of blood, possibly causing a potentially life- threatening anemia and growth restriction. If the recipient twin develops hydrops or the donor twin develops severe growth restriction, inadequate supply of oxygen (hypoxia) to the developing brain may occur during pregnancy or from respiratory distress syndrome (RDS) associated with early (preterm) delivery. As a result, brain damage may occur, potentially causing Cerebral Palsy. (For more information on this disorder, use “Cerebral Palsy” as your search term in the Rare Disease Database.)
When twin-twin transfusion syndrome occurs in mid-pregnancy, one of the fetal twins may die due to the effects of receiving too little blood, receiving too much blood, or having too small a share of the common placenta (severe placenta insufficiency). Blood may then pass from the live twin to the deceased twin, and the live twin may experience low blood pressure (hypotension) and/or inadequate blood flow to its tissues (severe hypoxia). Such decreased blood flow to certain areas of this fetal twin could be life-threatening or could result in a variety of developmental abnormalities, which might include malformations of the hands, arms, feet, and/or legs (terminal limb defects); underdevelopment of one side of the face (hemifacial microsomia); obstruction of the intestine (intestinal atresia); tissue damage and loss in the outer layer of the kidney (renal cortical necrosis); and/or a clot blocking an artery in the heart (coronary thrombosis). In some cases, severe injuries to the brain may occur, resulting in cysts or cavities in the brain’s outer layer (porencephaly) and/or absence of the brain’s cerebral hemispheres (hydranencephaly). (For more information on this disorder, choose “Hydranencephaly” as your search term in the Rare Disease Database.)
The exact cause of TTTS is not fully understood. However, it is known that abnormalities during division of the mother’s egg after it has been fertilized lead to the placental abnormalities that can ultimately result in twin-twin transfusion syndrome.
The normal development of identical (monozygotic) twins begins with the fertilization of the mother’s egg (ovum) by the father’s sperm. Within the first three days after fertilization, the fertilized egg (zygote) divides into two complete, identical embryos. These two embryos, which are nourished by separate placentas (dichorionic) during the pregnancy, ultimately develop into two individuals (monozygotic twins) who have almost identical genetic make-ups.
In some cases of monozygotic twin development, however, a zygote takes longer than three days to divide into two complete embryos. Scientists have observed that the longer it takes the zygote to divide, the more problems are likely to occur in identical twin pregnancies. If the zygote takes from four to eight days to divide, the twins share a common placenta (monochorionic) and the membrane that separates the fetal twins’ two amniotic sacs is thin (diamnionic). If the fertilized egg divides in eight to twelve days, the twins share a common placenta (monochorionic) and no dividing membrane is present; therefore, the two fetuses essentially share one amniotic sac (monoamnionic). Twin-twin transfusion syndrome has been reported to occur in both of these types of pregnancies (monochorionic-diamnionic and monochorionic- monoamnionic); however, the vast majority of cases of TTTS occur in monochorionic-diamnionic pregnancies. It is not understood why a zygote divides into twins nor why it takes longer than normal to divide in some cases.
In all monochorionic twin pregnancies, there are blood vessels in the shared placenta that connect the fetuses’ umbilical cords and blood circulations together (anastomoses). The placenta, which is connected to the fetuses by their umbilical cords, links the mother’s blood supply to her offspring’s. This enables the exchange of waste products from the fetuses to the mother for excretion and enables the transfer of oxygen and nutrients from the mother’s blood to the fetuses’. In most cases, the blood flow is relatively balanced through these connecting blood vessels. However, in twin-twin transfusion syndrome, the blood begins to flow unevenly through the anastomoses. Scientists do not understood what causes such an imbalance in blood flow to take place. However, it is believed that several different factors may play a role, including the degree to which the placenta may be unevenly shared by the twin fetuses, the type and number of connecting blood vessels (anastomoses) in the shared placenta, and changes in pressure within the mother’s uterus (such as occurs with polyhydramnios or with uterine contractions during delivery).
TTTS is a rare disorder that sometimes occurs when a mother is pregnant with identical (monozygotic) twins. There have been a few reported cases in which TTTS also affected identical triplets. Twin-twin transfusion syndrome affects approximately 5 to 15 percent of identical twin pregnancies, meaning that approximately 6,000 babies may be affected each year. However, it is difficult to determine the true frequency of TTTS in the general population since many cases are never diagnosed and many go unrecorded.
TTTS can be detected during mid-pregnancy (second trimester) by ultrasonography, an instrument that creates a fetal image by measuring the reflection of sound waves. Ultrasound findings that may indicate twin-twin transfusion syndrome include the presence of same-sex twins; a single, shared placenta (monochorionic), a thin membrane dividing the fetuses' amniotic sacs; differences in the amount of amniotic fluid with polyhydramnios (defined as a largest vertical pocket of fluid greater than 8 cm in the larger twin) and oligohydramnios (defined as a largest vertical pocket of less than 2cm in the smaller twin), and a size difference of greater than 20%. Present staging or classification of the severity of the disease currently follows that proposed by Quintero in 1999. This staging system has been a useful tool to allow physicians to compare treatment results and for choosing between different management strategies as it incorporates the worsening severity of the disease process in each of the increasing stages. It does, however, create the impression that the natural history of TTTS follows an orderly progression over time. Unfortunately, clinical experience has shown that this is not the case and progression of the disease processes are highly variable and somewhat unpredictable. This staging system also does not include elements describing the fundamental cardiovascular changes that are key to understanding the disease and are present in subtle forms even at the earliest stages of the disease process.
Examination of the placenta by physicians after delivery can confirm the twins' monochorionic status, the presence of connecting blood vessels (placental anastomoses), and the diagnosis of twin-twin transfusion syndrome.
The U.S. Food and Drug Administration in 2006 approved a device known as the Karl Storz Rigid TTTS Fetoscopy Instrument Set under its Humanitarian Device Exemption (HDE) program for the treatment of twin-twin transfusion syndrome. These are surgical tools that include a telescopic camera used to view a fetus (fetoscope) or placenta. These tools are used to identify and obstruct (photocoagulate) the connecting blood vessels (anastamoses) on the placenta using a laser thereby separating the flow of blood within the placenta for each of the twins. The instrument set is manufactured by a company headquartered in Germany, Karl Storz Endoscopy, Inc. The company's U.S. office may be contacted at:
Karl Storz Endoscopy-America, Inc.
600 Corporate Pointe
Culver City, CA 90230-7600
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When twin-twin transfusion syndrome (TTTS) is detected during pregnancy, different treatment options may be considered. Various treatment methods may be used to prevent the effects of TTTS in one or both fetal twins and to help manage symptoms that could result in premature labor and delivery. Immediate intervention may also be necessary after delivery.
If severely high levels of amniotic fluid occur during mid-pregnancy in the absence of other signs of TTTS, therapeutic amniocentesis (amnioreduction) may be recommended to restore amniotic fluid levels to normal. During this procedure, a needle is guided into the recipient twin’s amniotic sac, and amniotic fluid is withdrawn until the level is reduced to normal. In some cases, this procedure may need to be repeated several times before delivery. By restoring normal amniotic fluid levels, such therapy may promote more appropriate development rates for both twins and help prevent premature labor due to early rupture of the amniotic sac. In addition, decreasing the pressure in the uterus from too much amniotic fluid improves blood flow within the placenta and to each fetus.
While amnioreduction is no longer the mainstay of treatment for TTTS, it may still play a role in management in certain conditions. It may be a useful procedure to temporarily stabilize a patient to be transported to a center where more definitive therapy is available. It may be useful to decrease the size of the uterus where there is evidence of significant cervical shortening or dilation of the cervical canal to allow placement of a stitch around the cervix (cerclage) to prevent preterm delivery and allow laser therapy to be done. Or, it may be useful in managing symptomatic polyhydramnios when TTTS occurs after 26 weeks or when laser therapy is technically not possible.
Since the publication of the Eurofetus randomized trial comparing amnioreduction to selective laser photocoagulation, there has been no question that laser therapy is currently the optimal therapy for TTTS that develops before 26 weeks of pregnancy. Of all the available therapies, it is the one that seeks to interrupt the vascular connections on the surface of the placenta that are responsible for the development of the syndrome. In a 2004 study by Senat, et al, the group that underwent laser therapy had a significantly higher mean gestational age at delivery (33 versus 29 weeks) along with higher survival of at least one of the twins to 28 days of age (76% versus 56%). Follow-up of the surviving babies in this study showed that neurologic outcomes were also better in those that received laser therapy compared to those that were managed with amnioreduction, with a higher likelihood of being free of neurologic complications at 6 months of age (52% versus 31%).
Survival of one or both fetuses is only one aspect of the outcomes in TTTS. The average age of delivery even in sucessfully treated cases is still less than that seen in identical twin pregnancies without TTTS, and thus complications of prematurity still can impact significantly on long term outcomes. The frequency of long-term neurologic complications has been well documented in many case series, but one of the largest followed 145 babies from pregnancies that underwent laser therapy before 26 weeks of pregnancy. These children were followed for an average of just over 3 years of age and were categorized as having normal physical and neurologic development, minor neurologic deficiency or severe neurologic abnormalities leading to permanent disability based on standardized testing. This study by Graf, et al in 2006 found that 86.8 % had normal development, 7.2% demonstrated minor issues and that 6% had major neurologic abnormalities.
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