Can Twin-to-Twin Transfusion Syndrome Be Explained, and How Is it Treated?  GEOFFREY A. MACHIN, MD, PhD, and LOUIS G. KEITH, MDf The Permanente Medical Group. Oakland, California Northwestern University Medical School Chicago, llinois  What Are the Differences Between Monozygotic and Dizygotic Twins? Monozygouc twins (MZ) carry higher fetal and neonatal risks than dizygotic (DZ) twins. The risks are particularly evident when MZ twins are connected to a single i.e., monochorionic (MC), placenta. Interfetal vascular anastomoses (chorangiopagus) are present between the individual circulations. In contrast, all DZ twins and one third of MZ twins have dichorionic (DC) placentas, which may be separate or fused, but rarely, if ever, contain vascular connections. The MC placenta is a single (i.e., not fused) structure teleologically programmed to service the needs of a singleton embryo/fetus. It is not always capable of adapting to the circulatory demands of MC twins (or for that matter, triplets or quadruplets). Regardless of which therapy ultimately is used, it seems clear that better outcomes in MC pregnancies can be obtained only if TTS is actively anticipated, sought for, and diagnosed at the earliest stage of gestation, so that it might be treated before it causes irreversible fetal damage or death. Considerations such as these point to the desirability of unequivocal antenatal diagnosis of chorion status at the earliest possible time in multifetal pregnancy. This need is a compelling justification for ultrasonographic examination of all pregnancies at the first antenatal visit so that dating can be fixed and all multifetal pregnancies assigned either to the the relatively low-risk DC category or to the higher-risk MC or multifetal groups. If, conversely, the first ultrasound examination is delayed until 16-18 weeks, chorion status is more difficult to determine, and the opportunity already may have been missed to plan the successful management of TTS. How Common Are MC Twins And Their Complications? In a typical European/North American population, 30-40% of naturally conceived twins are MZ. Of these, two thirds are MC i.e., 20-27% of all twins are MC. It is wrong to assume that twins and multiple pregnancies resulting from attificial reproductive technology are necessarily multizygotic. Up to 10% of such gestations contain MZ twins, some of whom are MC. It is difficult to derive accurate prevalence figures for antenatal TTS because most cases are treated in referral centers. Only an approximate prevalence can be derived from unselected population studies. It has been stated that up to 35% of MC twins have TTS, but this figure likely represents an ascertainment bias. A figure of 10% seems more likely. The prevalence of intrapartum TTFS is unknown. Why Is MC Placental Vascular Anatomy Different and Therefore Dangerous? During early development, fetal and placental circulations arc established independently. Only later do they become connected via the umbilical cord and the chorionic plate. A "one-placenta/one fetus" relationship prevails in singleton pregnancies. The situation is more complex, variable, and unpredictable in MC twins, triplets, etc., because no fixed biologic principles are involved. Each MC placenta establishes a unique solution to connect the two fetal circulations. Vascular development apparently is an independent almost, random process, and there are ample opportunities for the formation of various intertwin vascular connections. In addition, the single MC placental parenchyma may be shared unequally between the twins, in terms of size of arterial and/or venous zones, and cord insertion (central/eccentric/marginat/velamentous) may influence asymmetric or unequal parenchymal sharing. lntertwin vascular connections are of two main types, superficial and deep (Fig l) Each has its characteristic flow and resistance pattern, by which it influences the fate of MC twin pairs. The detailed anatomy of vascular connections can be mapped postnatally by careful examination of MC placentas. Both the anatomy and physiology of these connections may change throughout gestation, however, as evidenced by rare cases in which TTS resolves spontaneously as well as those cases that are treated successfully. Therefore, the postnatal topography of vessels in MC placentas provides at best, only a partial picture of their prenatal structure and function. Superficial connections form between vessels of like type, i.e., they are arterioarterial (a-a) and venovenous (v-v) These are end-to-end anastomoses that are readily visible as they meet above the chorionic plate; they are not usually the structural basis for antenatal TTS. In fact, they usually act to protect twin pairs who might otherwise develop TTS. In the North American population, a-a connections are far more than v-v connections; in a-a and v-v connections, there is little or no net flow when both twins have equal cardiac outputs, and there is no coexistent a - v anastomosis [see below]. The a-a connections are so frequent that the arterial circulations of an MC fetal twin pair function almost as one syncytial vascular system. In contrast, the v-v connections are relatively uncommon and operate at lower pressures and resistances than arteries; hence, large blood volumes may be transferred rapidly between twins. For this reason, v-v anastomoses commonly are associated with poor outcomes, regardless of whether they are present alone or in combination. Deep in the parenchyma, the "third circulation" may develop. The A - V anastomosis represents a zone of placental parenchyma that is supplied with umbilical arterial biood from one twin (the donor), but from which venous blood is inappropriately returned to the other twin (the recipient) instead of to the donor twin. This type of anastomosis is not present on the chorionic plate. Because of the arteriovenous pressure gradient, net flow always occurs in an A-V anastomosis. Indeed, when this is the only placental circulatory connection between twins, the onset of antenatal TTS is not only predictable but inevitable. Fortunately, solitary A - V anastomoses occur only rarely, and the most common combination of anastomoses is the coexistence of an a-a with an a - v connection. In this pattern net a - v transfusion is likely to lower donor blood pressure and raise recipient pressure. A dynamic equilibrium thus is established in which unidirectional flow in the a-a anastomosis back from recipient to donor compensates for the net a - v transfusion. It is important to note that a-a anastomoses are seldom harmful in themselves; on the contrary, they protect the twins from the harmful effects of a - v connections that otherwise can prove disastrous. Most MC placentas have simple vascular patterns that are analyzed easily. With few exceptions, the anatomic substrate for antenatal TTS is an MC placenta with a zone of a - v perfusion only (i.e., with no other anastomoses). Arterial and venous vessels of a given cotyledon penetrate the chorionic plate in close proximity; this is true whether they are both normally connected to one of the twins or when they form an (inappropriate) a - v connection between the twins. (This fact is relevant to mapping of vessels for laser occlusion.) In effect, an a - v anastomosis is defined as a placental zone in which an arterial branch of the donor twin is not accompanied by a venous branch for that twin; at the same time, the venous branch returning to the recipient twin is not accompanied by a corresponding arterial branch from that twin (Fig. 1).  What Is the Underlying Pathophysiology of Antenatal TTS? Twin-to-twin ttansfusion syndrome was originally described postnatally; some MC twins were noted to be growth discordant, with the smaller (donor) twin being pale and the larger (recipient) twin being plethoric and occasionally having some degree of hydrops fetalis. It soon became clear, however, that: 1) not alI TTS twins are growth discordant; 2) not all growth discordance in MC twins is caused by TTS,' 3) sometimes the smaller twin is plethoric (because of acute perinatal TTS); and 4) there are additional causes of fetal morbidity and mortality in MC twins that may mimic TTS The antenatal diagnosis of TTS is neither easy nor always satisfactory, partly because correlations with postnatal status are confounded by the separate clinical presentations of TTS: a) the chronic, antenatal type that can begin as early as 13 weeks and is often fully developed by 20-22 weeks of gestation; b) the acute. intrapartum type that happens in the interval between the clamping of the cords of the first-born and second-born MC twins. In some twin pairss, both phenomena occur, and they may actually flow in opposite directions, such that the chionic antenatal donor becomes the acute perinatal recipient. Chronic antenatal TTS usually is caused by net transfusion via a - v anastomosis in the absence of any other (compensatory) anastomosis. It is not known what volume of transfused blood is required to initiate the train of events; it is probably quite small, but may be repetitive or continuous for a period of days. Typically, the donor is noted to be growth-retarded from the earliest stage. Often this is because the cord is velamentously inserted and the donor has access to a smaller proportion of the placenta than the recipient. Stated another way, the initial growth discordance is nutritional in origin, whatever the subsequent transfusion events may be. The donor therefore is biophysically disadvantaged and may be hypertensive; this increases the likelihood of net a-v (and/or a-a) blood donation to the recipient. Arterial hypoperfusion of the viscera (and of the kidneys in particular) may occur, leading to oligohydramnios At the sarne time, the recipient becomes hypervolemic and compensates for this with polyuria, producing hydramnios. Whereas TTS is a progressive pathophysiologic process of unknown duration, the clinical onset of hydramnios is often abrupt and exceedingly dramatic, with maternal abdominal discomfort and respiratory distress, premature rupture of membranes, and/or preterm labor. When hydramnios reaches this severity, the chance of effective intervention for fetal salvage is virtually nonexistent. In contrast, presymptomatic oligohydramnios/hydramnios is detectable if anticipated by early and frequent sonography of identified MC twin pregnancies. The polyuric response of the recipient does not solve the problem; low molecular weight plasma constituents can be eliminated in the renal ultra filtrate, but blood cells and higher molecular weight plasma proteins are retained resulting in increased blood viscosity In this manner, peripheral vascular resistance rises, right ventricular hypentrophy develops, and cardiac failure often results in tricuspid incompetence and hydrops fetalis with ultimate fetal death. Although the donor is initially the more stressed of the fetuses, the recipient often dies first. The death of the recipient abruptly releases its area of the placenta for perfusion by the surviving donor, who is unable to undertake this task without developing significant hypotension. This causes either peripheral vascular shutdown, with infarcton of many organs, including brain, kidneys, spleen, and extremities. Fetal death may follow, or a highly compromised neonate may be born. This predictable sequence mandates that any intervention to increase fetal survival must be carried out before the death of the first twin. Multi-organ infarction occurs rapidly after the death of the first fetus, and delayed intervention will not prevent organ damage to the survivor. Therapeutic options are influenced by gestational age. Recipients who survive into the neonatai period may have lethal residual heart disease, with massive right ventricular hypertrophy, pulmonary stenosis, and endocardial fibroelastosis, all resulting from abnormal blood viscosity and blood flows in fetal life. Brain damage also has been reported in recipient survivors. It is now becoming clear that such lesions result from abnormal cardiovascular dynamics rather than from the thromboembolic events that were previously thought to follow the fetal death of one twin. Careful ultrasonographic observations of these infarctive events show that they occur early, are progressive, and can he documented before the death of the co-twin.  How Do You Diagnose TTS Antenatally? The criteria for the diagnosis of TTS are not clear cut. They have expanded dramatically with the increasingly sophisticated use of ultrasound in recent years. With minor variations, they include most of the following. 1. Proven monochorionicity, 2. Hydramnios/oligohydramnios. 3. Growth discordance (may not be always present), 4. In the recipient twin; a) larger umbilical cord, abdominal circumference, kidneys and bladder, with     measured polyuria over time. b) large, hypodynamic heart with tricuspid incompetence, c) dilated inferior vena cava. ductus venosus, umbilical vein with abnormal flow patterns. d) abnormal systemic arterial flow patterns. e) rapid recurrence of hydramnios after amniocentesis. 5. In the donor twin: a) peripheral vascular shutdown with oligohydramnios, abnormal Doppler Studies of venous and arterial flows. b) biophysical improvement after amniocentesis. c) smaller abdominal circumference with small cord, often velamentously inserted. 6. Discordant hematocrit and plasma protein levels by cordocentesis (may not always be present). 7. Transfer of intravascutarly injected adult red blood cells from donor lo recipient. 8. Temporary paralysis of both twins after intravascular pancuronium infusion of one twin. 9. Elevated erythropoietin levels in both twins, and 10. Elevated atriopeptin level in recipient twin.  What Is Acute Perinatal TTS? Acute perinatal TTS occurs in the interval between the clampings of the cords of the first-born and second-born twins. During this period, the second-born twin has the sole connection to the entire placenta and may receive a significant transfusion. In cases of antepartum TTS, the larger, recipient twin usually is born first; therefore, the second-born antenatal donor with oligohydramnios is born paradoxically plethoric because of an acute perinatal transfusion. At the same time, some MC twin pairs without antenatal TTS also undergo acute perinatal TTS, which may be sufficiently severe to require treatment, e.g., partial volume exchange transfusion in the recipient and transfusion with packed erythrocytes for the donor. Rarely does the second-born twin lose blood into the placenta before its cord is clamped. An acute perinatal transftision has the opposite effect of fetal death of one MC twin because it is in the opposite direction. Acute perinatal hemodynamic change also could result from acute fetomatemal hemorrhage. Acute perinatal transfusion should be considered in making decisions about the likely interval time between the births of the twins. What Are the Treatment Options for Antenatal TTS? In contrast to the dire opinions of the older literature, several recently published case series of aggressive therapeutic amniocentesis have suggested that: 1) survival potential for treated fetuses is considerable (52%); and 2) up to 20% of untreated fetuses also may survive. These figures do not consider neonatal morbidity, nor are they stratified by gestational age of onset of TTS or by severity of hydramnios. Multiple repeated procedures usually are required, although occasional permanent improvement has been noted afier a single amniocentesis. Serial amniocentesis results in substantially higher survival rates, and these results conceivably could improve with earlier diagnosis and intervention, as well as with better case selection. It is not clear how amniocentesis works, because, at first sight, it does not specifically correct the underlying anatomic problem, i.e., the presence of an uncompensated a - v anastomosis. It seems likely, however, that amniocentesis does considerably more than merely buy time for fetal maturation. The main threat to the twins is the development of rnassive hydramnios in the sac of the recipient. This hydramnios affects placental vascular dynamics in five ways: 1. The attachment of the septal membranes to the placental surface can shift. The donor twin is tightly invested by annion, which usually is not visible on ultrasound and is described as "stuck". If the septal attachment shifts away from the recipient and toward the donor, the high pressure of the recipient's amniotic sac can be transmitted to some of that portion or the MC placenta suplying the donor. Manometric measurement of arriniotic fluid pressure before therapeutic amniocentesis indicated that opening amniotic cavitary pressure easily exceeds the pressure in the veins of the chorionic plate and umbilical cord. Therefore, the high pressure of hydramnios may cause further reduction of the venous return to the donor by obliteration of venous branches on the chorionic plate, thereby worsening its biophysical status. 2. In the recipient, it is only the presence of tricuspid regurgitation and increased pressure in the ductus venosus and umbilical vein that allow its extrafetal veins to remain patent. 3. A further consideration is the fact that any compensatory v - v anastomosis coexisting with the a - v anastomosis could be shut down by the increasing pressure of hydramnios. 4. It has been reported that some MC twins with antenatal TTS have one or both cords velamentously inserted into the septal membranes. With pressure-induced septal shift, these velamentous vessels may be stretched or even occluded. 5. The placenta "plumps up" to resume its normal thickness and shape after therapeutic amniocentesis. This suggests that relationships between chorionic plate vessels and parenchyma are distorted by hydramnios, interfering with uteroplacental function for both twins. Amniocentesis may be beneficial by reducing amniotic cavitary pressure, re-opening V - V anastomoses, relaxing velamentously inserted umbilical vessels, and correcting the distorted shape of the placenta. Its effects probably go far beyond the mere prolongation of pregnancy. In those cases where amniocentesis is not able to arrest the progress of the disease, fetoscopic laser occlusion of chorionic plate vessels may offer an anatomically precise method of dealing with a - v anastomosis. Two series have been published. The methodology for vessel coagulation varies. De Lia et al. advocated coagulation at the placental vascular equator or interfetal membrane septum edge, whereas Ville et al preferred to coagulate systematically along the whole length of the intertwin membrane. Not everyone agrees that laser coagulation assures results equivalent to or better than those from serial amniocentesis. Because amniocentesis, tocolysis and indomethacin are all part of the protocol for laser coagulation, it is not presently possible to isolate the specific effect of coagulation. Criteria for success after vascular coagulation include the cessation of polyuria (and hydramnios) in the recipient and evidence of biophysical improvement in the donor. It is questionable whether the donor should be expected to exhibit catch-up growth especially in the presence of unequal placental parenchymal sharing. In selecting potential methods of treatment for antenatal TTS, measurement of initial amniotic fluid pressure may be important in identifying those cases in which amniocentesis will probably suffice (<17 mm Hg) and those with higher values in which additional methods such as vessel coagulation or selective termination, also may be indicated. Assuming that high amniotic cavitary pressures of the recipient sac are transmitted directly to the sac of the donor there seems little advantage to deliberately disrupting the membranous septum. This exposes the twins to the increased risks of cord accidents caused by monoamnionicity. In a series of nine cases of twin-twin transfusion with "stuck twin," amniocentesis and septal puncture resulted in increased fetal movement and umbilical artery velocimetry in the stuck twins. The fetal survival was 83%, and there were no cord entanglements. The effect may resemble amniocentesis in that it moves the septal membranes back to a more normal position, it is difficult to see how this technique improves the status of the fetal vascular anastomoses. The threat of cord entanglement remains. Does TTS Account for All the Morbidity and Mortality of MC Twins? The prevalence of TTS in MC twins is not known with certainty, so this question cannot be answered easily. There are other causes of morbidity and mortality in MC twins; cord complications (especially in monoamniotic twins) are well known, and it is thought that the prevalence of major malformations is higher in Mz (and, possibly, MC) twins than in DZ twins and singletons. But these events are rare. Standard obstetric complications do occur in MC twins, e.g. antepartum hemorrhage and cord accidents. Nevertheless, TTS is probably the main cause of adverse outcomes in MC twins. What of the Future? The perinatal outcomes of twins are all too infrequently analyzed by method of conception (natural or assisted) and chorionicity (or zygosity). This circumstance is totally unsatisfactory, in view of the known higher prevalence of complications in MC twins. We strongly advocate antenatal assessment of chorionicity and that all placentas of twins and multifetal pregnancies have their chorion status confirmed in the delivery room and/or the pathology laboratory. Population-based studies then can assess the true prevalence of TTS and other complications of MC twinning. These data then could be used to alert health professionals to the real likelihood of encountering and treating these complications. Regionalized tertiary care could be organized. Pediatric follow-up probably is obtained best in special "twin clinics". The accumulation of population-based clinical data on TTS through a special registry would allow analysis of the outcomes of TTS. Methods may be developed to map precisely the placental vascular anastomoses before carrying out procedures. In this way, cases could be selected for amniocentesis or laser coagulation therapy. In addition, vessels could be coagulated selectively on the basis of their participation in anastomoses.