Monochorionic twinning is a type of gestation in which the fetuses share a single chorion (the outer membrane) and may or may not share the amnion (the inner membrane). Vascular anastomoses are found in almost all monochorionic placentas. Thus, interfetal transfusion is a normal event in monochorionic twin pregnancies. When intertwin transfusion in monochorionic twins is balanced, clinical manifestations of twin-to-twin transfusion syndrome do not occur.
Bajoria and coworkers (1995)27 suggested that twin-to-twin transfusion syndrome resulted from an unbalanced intertwin transfusion due to uncompensated arteriovenous anastomoses (Figure 13-26). Pregnancies affected by twin-to-twin transfusion syndrome had fewer arterio-arterial anastomoses (Figure 13-27) present (24% versus 84% of monochorionic twins without twin-to-twin transfusion syndrome).28 Seventy-eight percent of monochorionic pregnancies in this series with 1 or more arteriovenous anastomoses and no arterio-arterial anastomoses developed twin-to-twin transfusion syndrome.28 When an arterio-arterial anastomosis is found, the risk of developing twin-to-twin transfusion syndrome is reduced 9-fold.
A: The arrow points to an arteriovenous anastomosis in a monochorionic diamniotic placenta. Note the darker color of the artery crossing over the vein. (Courtesy of O. Brandão.) B: Digested cast representing an arteriovenous anastomosis in a monochorionic diamniotic placenta. (Courtesy of P. Nunes.)
Arterio-arterial anastomosis put on evidence by color Doppler in a monochorionic diamniotic twin pregnancy.
Monochorionic twins have a continuous spectrum of severity in the imbalance between their fetoplacental circulations, depending on an angioarchitectural basis, and hemodynamic and hormonal factors. Blood is transfused from the donor to the recipient via vascular connections (Figure 13-28). The donor becomes anemic, hypovolemic, growth restricted, and develops high-output cardiac insufficiency and oligohydramnios as a consequence of reduced urinary production. In contrast, the recipient develops circulatory overload with congestive heart failure and polyhydramnios. The elevated urinary production from the recipient twin leads to polyhydramnios and an overdistention of the amniotic cavity, which compresses the donor and its vascular supply against the uterine wall, further decreasing perfusion to the donor fetus. The reduction in amniotic fluid on the donor side results in a close apposition of the intertwin membrane that fixes the donor fetus to the uterus, a condition known as "stuck twin" (Figure 13-29). The process takes several weeks and an intermediate stage is the "folding membrane" sign, in which a redundant membrane progressively collapse over the donor. During this stage, folds can be seen in the membrane. Because there is no loss of protein or cellular components from its circulation, colloid osmotic pressure draws water from the maternal compartment across the placenta, establishing a vicious cycle of hypervolemia, polyuria, and hyperosmolarity, leading to high-output cardiac failure, hydrops, and polyhydramnios.
In twin-to-twin transfusion syndrome (top drawing; note the artery-to-vein connection), the donor twin (left) becomes anemic, hypovolemic, and growth restricted, and as a consequence has reduced urinary production. Because swallowing of the fluid is not impaired, the amniotic fluid volume progressively decreases (yellow lines represent the interamniotic membrane). Conversely, the recipient twin (right) becomes hypervolemic. The elevated urinary production from the recipient twin leads to polyhydramnios and an overdistention of the amniotic cavity, which compresses the donor and its vascular supply against the uterine wall, further decreasing perfusion to the donor fetus. The end condition is the "stuck twin" (lower drawing).
As the transfusion progresses, the donor twin loses more fluid and the recipient produces more. The net effect is that the membranes become closely apposed to the donor twin.
Therefore, twin-to-twin transfusion syndrome reflects primarily a pathological form of circulatory imbalance that develops chronically between hemodynamically connected monochorionic twin fetuses. It affects about 5% to 15% of monochorionic twin pregnancies (1:400 pregnancies). This syndrome accounts for 17% of perinatal mortality, nearly 12% of neonatal deaths, and 8.4% of infant deaths in twins. This is 3 to 10 times higher than that attributed in singletons.
Though dramatically devastating and clinically identifiable, this condition is still far from being effectively anticipated and treated. Classically it is defined as follows:
Affecting two babies, not one
Affecting structurally normal babies
The pathological epicentre being in the placenta, not in the babies
Being associated with important perinatal morbidity and mortality
Being amenable to curative therapy
The net result of transfusion between twins depends on the following:
Vascular anastomoses: Combination of type of connections (number, type, and diameter) and direction of connections.
Placental sharing: Unequal placental sharing, both by discrepant size of placental territory "distributed" to each fetus or by velamentous insertion of umbilical cord, may further impair growth in twin-to-twin transfusion syndrome fetuses.29
Asymmetry in the progressive reduction of an initially large number of bi-directional AV connections formed during the embryonic unification of placental and fetal vessels.
Unbalanced renin-angiotensin system (RAS): Upregulation of RAS (donor) and downregulation of RAS (recipient) with transfer of angiotensin II may cause or contribute to the development of twin-to-twin transfusion syndrome.
Incomplete remodeling and defective trophoblastic invasion of maternal spiral arteries.
Diagnosis of Twin-to-Twin Transfusion Syndrome
In the past, diagnosis of the syndrome was made only after delivery and the standard neonatal criteria included the following:
Danskin and Neilson (1989),30 revisiting the neonatal criteria for diagnosis of twin-to-twin transfusion syndrome, concluded that these findings were recorded both in monochorionic and DC twins at similar rates.
Considering the more consistent and useful sonographic antenatal criteria,31,32, and 33 the emphasis of screening and diagnosis of twin-to-twin transfusion syndrome was pushed backwards in pregnancy, based on the following criteria (Figures 13-30,13-31,13-32,13-33,13-34, and 13-35):
The difference in the size of the cord is clearly visible.
The anastomosis is occasionally visible. (Courtesy of Dr. G. Pilu.)
Combination of discrepancy in size, amniotic fluid volume, and bladder volume observed in a case of twin-to-twin transfusion syndrome.
Before the donor twin becomes stuck, a typical intermediate stage is the "folding membrane" stage, where the redundant membrane progressively folds as it wraps itself around the donor.
At some point, the "folding membrane" stage could resemble amniotic band syndrome. Awareness of the condition will prevent a misdiagnosis.
The typical appearance of the "stuck twin" immobilized in a portion of the uterus.
Discordance in amniotic fluid volume (oligo-polyhydramnios sequence)
Twin-to-twin transfusion syndrome is understood as an ultimate manifestation of a hydrodynamic imbalance. Fetal renal perfusion is asymmetric: the congestive heart failure in the recipient will overperfuse the kidneys with consequent polyuria and excess of amniotic fluid; hypovolemia in the donor causes in adequate perfusion of the kidneys with decrease in urinary output and oligohydramnios.33 In order to uniformize amniotic fluid volume criteria, a quantitative definition was proposed33:
Polyhydramnios in 1 sac, with a deepest vertical pool of amniotic fluid of at least 6.0 cm at less than 20 weeks of gestation, 8.0 cm at 20 to 22 weeks, and 12.0 cm at 23 to 25 weeks. The polyhydramnios should be related to polyuria, with a distended fetal bladder during most of the examination period.
Oligohydramnios in the other sac, with a deepest vertical pool of amniotic fluid of at most 2.0 cm. The oligohydramnios should be likely related to fetal oliguria, with a collapsed bladder during most of the examination period. Not infrequently anhydramnios in the donor sac results in it becoming "stuck," shrouded by the intertwin membrane, while the recipient's sac becomes severely polyhydramniotic.
One should bear in mind that sonographic pitfalls may exist in the presence of discordant anomalies in twins that imply differences in amniotic fluid volume, such as one twin with esophageal atresia and consequent polyhydramnios, or with renal agenesis, with consequent olygohydramnios/anhydramnios.
Concurrent confirmatory features include a small or nonvisible bladder in the donor, along with an enlarged urinary bladder by excessive micturition in the recipient.
Discordance in fetal size
Discordant growth is a common complication of twin pregnancies. Abdominal circumference rather than head measurements of twins was proposed as the most reproducible and meaningful parameter. A difference in abdominal circumference between twins of more than 20% indicate clinically significant growth discordance.
Abnormal Doppler findings
Alterations in cardiac hemodynamics are indirectly put on evidence by Doppler. The recipient presents with pulsatility in the umbilical vein and absent or reverse flow in the ductus venosus34 as signs of congestive heart failure due to hypervolemia and increased preload from placental vascular anastomotic transfusion (Figure 13-36).
Zosmer et al (1994)35 showed that some surviving twins of twin-to-twin transfusion syndrome had a persistent right ventricular hypertrophic cardiomiopathy and proposed that cardiac dysfunction could be induced in utero by sustained strain upon the heart by twin-to-twin transfusion syndrome, predominantly affecting the right ventricle.
In contrast, the significant reduction of blood flow velocity in the umbilical artery recorded in the "donor" is consistent with hypovolemia and increased placental resistance, increasing cardiac afterload, and decreasing umbilical venous return. Abnormal Doppler systolic/diastolic ratio at the umbilical cord (>0.4), and the absent end-diastolic flow in the donor's umbilical artery and the absent or reversed flow in the ductus venosus of the recipient's are usually associated with a poor prognosis.186, 187, 188, 189, 190, 191 and 192
Both donor and recipient twins have volume/pressure-loading imbalance between the circulations during cardiovascular development, creating a hostile intrau-terine environment. Echocardiography allows assess-ing the cardiovascular adaptation with recognition of the alteration of function and evolution of antenatal management.
In the study by Fesslova et al (1998),36 all recipient fetuses showed cardiac hypertrophy and dilatation. The cardiac involvement in recipient twins was of variable severity, ranging from biventricular hypertrophy and dilatation to impaired contraction, with massive signs of tricuspid regurgitation and hydrops fetalis.
After birth about half of the recipients showed biventricular hypertrophy, with prevalent left ventricular hypertrophic cardiomyopathy.35,36, and 37 A smaller subgroup will develop right ventricular tract obstruction (functional pulmonary stenosis) and pulmonary hypertension in the neonatal period, which may be aggravated by systolic right ventricular dysfunction. Recently, diastolic abnormalities were described in the right ventricle, with abnormal filling patterns, prolonged isovolumic relaxation time, and abnormal flow patterns in the inferior vena cava and ductus venosus.
Abnormalities of vascular distensibility were described in survivors of twin-to-twin transfusion syndrome in infancy. The donor fetus shows evidence of chronic hypovolemia resulting in upregulation of the renin-angiotensin system. Transfer of increased concentrations of angiotensin II will probably cause increased vascular stiffness in the surviving donor in childhood.
Signs of hydrops in the recipient twin
Hydrops or evidence of congestive heart failure of either twin may appear as a sign of TTTS, although these findings are more common in the recipient twin.
Other ultrasonographic findings
Velamentous insertion of the cord is a frequent finding.
Funipuncture. Although it allows the intertwin hemoglobin difference assessment, the degree of fetal anemia in the donor twin and the twin's zygosity through blood group studies, those benefits are not justified by the risk of the procedure.
Differences in echogenicity (ultrasound) and in color (after delivery) of the placentas: due to blood transfusion from one twin to the other, the placenta of the donor twin tends to be whitish ("pale") and the placenta of the recipient of a denser color (excess of blood).
In twin-to-twin transfusion syndrome Doppler laterations are recorded in a fully established syndrome: absent or reverse end-diastolic flow in the umbilical artery in the donor; absent or reverse A wave in the ductus venosus of the recipient. (Courtesy of K. Nicolaides.)
In summary, in the most severe forms, the diagnosis of twin-to-twin transfusion syndrome should not be difficult: a single placenta, same fetal sex, massive polyhydramnios in the sac of the recipient twin, and a stuck donor twin squeezed against the uterine wall with obvious growth discordance. However, milder forms of the disease are more difficult to diagnose because of the lack of uniform criteria; twin-to-twin transfusion syndrome should be suspected in the presence of amniotic fluid discrepancy between the cavities, regardless of the weight discrepancy between the twins.
When death of both fetuses occurs as the end result of twin-to-twin transfusion syndrome, the necropsic examination provides additional information, showing clear discrepancies in size and color (shorter and pale, the donor; and bigger and reddish, the recipient) (Figures 13-37 and 13-38).
Macroscopic specimens of twin-to-twin transfusion syndrome with intrauterine death: we can see the recipient, bigger and with larger viscera, and the donor, smaller and with smaller viscera (heart, kidneys, and lungs). In apparent contradiction with the expected characteristics of both donor and recipient, the recipient is paler and the donor is pletoric due to an acute reversal of the intertwin transfusion, with death of the donor first. (Courtesy of O. Brandão.)
Macroscopic appearance of the placenta from the donor twin (smaller and paler) and from the recipient (bigger, heavier, and darker). Looking at histology, we can observe edematous and immature villi with numerous Hofbauer cells, with capillaries full of erythroblasts in the placenta of the donor; in the recipient, we can observe mature villi with intense congestion. (Courtesy of O. Brandão.)
Twin-to-twin transfusion is a disorder of the second trimester. We are not aware of any report in the literature of the condition occurring in the third trimester. In the third trimester a form of acute twin-to-twin transfusion may develop in twins with a balanced hemodynamic situation. This can occur when an arterio-arterial communication that maintained the balance between the twin abruptly occludes. The transfer no longer compensate on a high flow arterio-arterial communication but only on lower transfer arterio-venous communication.
Basically, the prognosis depends on the stage of the pregnancy at which the disease manifests and the severity of the circulatory imbalance. When signs of twin-to-twin transfusion syndrome are seen early in gestation there is a higher risk of perinatal morbidity and mortality.7 Intrauterine hypoxia, preterm delivery, and death of one fetus (usually the donor) with subsequent death or hypoxia/ischemia in the surviving twin are the most common complications to watch for in these pregnancies.
Aggressive treatment appears to be more successful than conservative medical management. For many years, the most employed technique has been amniodrainage of the recipient amniotic sac by serial amniocentesis.38 The aim of amniodrainage was to restore the normal amniotic fluid volume and thereby decrease the pressure on the donor vasculature, improve its perfusion, and decrease the risk of polyhydramnios-induced preterm labor and thus prolong the pregnancy. The number of amniocenteses and volume of fluid drained differed, depending on the severity of the polyhydramnios, degree of fetal compromise, and maternal symptoms. Approximately 1 L of amniotic fluid should be removed for every 10 cm of amniotic fluid index elevation.
Amniodrainage, however, only temporarily corrects the symptoms and does not alter or interrupt the pathologic chain of events responsible for the condition. Perinatal survival with amniodrainage is quoted as 61 ± 22% with a risk of serious neurologic handicap in 19 ± 5% of the survivors. More recently, ablation of communicating vessels on the placental surface by neodymium YAG laser guided by fetoscopy has been proposed.39,40,41,42,43,44, and 45 The aim of this technique is to interrupt the abnormal placental vascular communications between the twins selectively.46 Although the survival rate between amniodrainage and fetoscopy is not very different, studies suggest a significant decrease in neurologic handicap among survivors submitted to fetoscopy (Table 13-3). Surgical endoscopic treatment proved beneficial in a randomized controlled trial. Over 1300 cases from 17 publications showed a median perinatal survival rate of 57% (50% to 100%); brain lesions were present in 2% to 7% of the survivors at the age of 1 to 6 months. The overall survival rate at birth was 66% (1894 of 2869). The percutaneous technique has gained wide acceptance, with an acceptable risk of maternal morbidity but a significant risk of miscarriage or preterm rupture of the membranes, presenting in 6.8% to 3% and 5% to 30%, respectively.45,46 However, variations in survival rates between centers and inconsistency in the reporting of complications call for more homogeneity in the pre- and postoperative assessment.45,46
Table 13-3MANAGEMENT OF TWIN-TO-TWIN TRANSFUSION SYNDROME BY LASER COAGULATION ||Download (.pdf) Table 13-3 MANAGEMENT OF TWIN-TO-TWIN TRANSFUSION SYNDROME BY LASER COAGULATION
|Author(s), Year ||Study Design ||Number of cases ||Technique ||Survival of Both Twins ||Survival of 1 Twin ||Death of Both Twins ||Neurological Handicap of Survivors |
|De Lia, 199547 ||Case series ||26 ||Nd:YAG laser ||34.6% (9/26)a ||34.6% (9/26) ||30.8% (8/26) ||4% (27/28) |
|Ville et al, 199840 ||Case series ||41 ||Nd:YAG laser ||36.5% (15/41) ||41.5% (16/41) ||22% (10/41) ||6.5% (3/46) |
|Hecher, 199948 ||Comparative study ||116 || |
Nd:YAG laser (n = 73)
(n = 73) vs serial
(n = 43)
|De Lia et al, 199942 ||Case series ||67 ||Nd:YAG laser ||56.7% (38/67) ||25.4% (17/67) ||17% (12/67) ||4.3% (8/44) |
|Senat et al, 200444 ||Randomized ||144 ||Nd:YAG laser vs serial amniodrainage ||36% (26/72) ||40% (29/72) ||24% (17/72) ||5% (4/88) |
Although some investigators have advocated intentional rupture of the intervening membrane (amniotic septostomy) to equalize the volume of fluid in both sacs,49 but it has been argued that artificial normalization of the fluid volumes with septostomy would not change the hemodynamic status of the fetuses and disruption of the membranes could lead to death of the fetuses from cord entanglement.46 Ligation of the umbilical cord of the donor twin and maternal treatment with indomethacin or digoxin have also been proposed as therapeutic options in selected cases. Further information on treatment can be obtained at www.fetalmed.com.
It should be noted, however, that even a rapid delivery (30 minutes) after the demise of one twin, does not always protect against brain injury.21
The differential diagnosis should mainly include twins of discordant size that do not have the transfusion syndrome as the underlying pathophysiologic mechanism for the problem. Some investigators have proposed a new entity called twin oligohydramnios–polyhydramnios sequence33 of which twin–twin transfusion would be part. Histopathologic studies of the placenta are required to differentiate twin–twin transfusion from the other conditions included in twin oligohydramnios–polyhydramnios sequence. Isolated IUGR can be considered if the growth discrepancy is less than 15% and the other features of the syndrome are not present. Dichorionic twin pregnancy with fused placentas and growth restriction of one of the fetuses is another condition that can lead to misdiagnosis. This can be excluded if the twins have different sexes or after birth by histopathologic analysis of the placenta. Other differential diagnoses to be considered are TORCH infections restricted to one twin, asymmetric chorionic development, fetomaternal hemorrhage, abruption, agenesis of the ductus venosus, and bilateral renal agenesis.
The overdistention of the uterus caused by polyhydramnios can cause preterm labor, amniorrhexis, abruptio placentae, and maternal respiratory and abdominal discomfort. Death of one twin is associated with at least a 25% risk of death or a 50% neurologic handicap of the surviving twin. Although the cause of neurologic handicap has usually been attributed to embolization, currently accepted evidence indicates severe and sudden hypotension with "draw back" of the recipient blood into the dead fetoplacental unit as the causative factor.19,20, and 21
Prediction of Twin-to-Twin Transfusion Syndrome
Clinically predicting twin-to-twin transfusion syndrome is more important than diagnosing the syndrome. Therefore, targeted surveillance of monochorionic twins at earlier stages of gestation could anticipate and provide timely management of the pregnancies at risk of the devastating twin-to-twin transfusion syndrome.
Data gathered from the literature show that increased nuchal translucency thickness (NT) at 10 to 14 weeks of gestation was found twice as frequently in monochorionic than in singleton pregnancies, and the likelihood ratio of developing twin-to-twin transfusion syndrome in those twins with increased NT was 3.5.50,51 Considering that monochorionic pregnancies do not show a higher prevalence of chromosomal abnormalities, the higher prevalence of increased NT in those twins could be ascribed to the early establishment of cardiac dysfunction. With advancing gestation, this transient heart failure eventually resolves with increased diuresis and ventricular compliance.
It was observed that whenever the discrepancy of NT values was above 20%, the detection rate for early fetal death was 63%, and for severe twin-to-twin transfusion syndrome it was 52%.52 If the discordance was less than 20%, the risk of complications was less than 10% (Figure 13-39).52
Monochorionic diamniotic twin pregnancy at 12 weeks of gestation. Nuchal translucency measurements were discrepant (1.47 mm and 2.32 mm). Eventually the fetuses developed twin-to-twin transfusion syndrome at 16 weeks and a laser ablation of the anastomoses was performed.
Studies from Matias et al demonstrated that abnormal DV blood flow in the first trimester of pregnancy (11-14 weeks) was more frequently found in foetuses affected by chromosomal abnormalities or cardiac defects, as an indirect sign of cardiac insufficiency/dysfunction.53,54,55, and 56 More recently and following this reasoning, Matias et al demonstrated in a study of 99 monochorionic diamniotic pregnancies at 11 to 14 weeks of gestation, that twin-to-twin transfusion syndrome eventually developed in those fetuses which combined increased NT and abnormal flow in the ductus venosus (DV). The presence of at least one abnormal blood flow waveform in the DV was associated with a relative risk for developing TTTS of 11.86, with a sensitivity of 75% and a specificity of 92%. The combination of abnormal DV flow with NT discrepancy 0.6 mm yielded a relative risk for the development of TTTS of 21.57,58
Growth Discordance in the First Trimester of Pregnancy
Monochorionic twins who ultimately develop twin-to-twin transfusion syndrome may exhibit intertwin difference in growth as early as 11 to 14 weeks of gestation.59 Though the relationship between the first trimester intertwin growth discordance and the outcome of these pregnancies is still controversial, early discordance of more than 10% in crown-rump length should heighten fetal surveillance.
The search of arteriovenous anastomoses in the placental plate of monochorionic placentas by color Doppler (Figure 13-40) has until now mainly provided a negative value: only 5% of monochorionic twins will develop twin-to-twin transfusion syndrome if arteriovenous anastomoses are present; if absent, 58% will develop twin-to-twin transfusion syndrome. The sensitivity and positive predictive value for absent arteriovenous anastomoses in predicting twin-to-twin transfusion syndrome was 74% and 61%, respectively.60
Arterio-arterial anastomosis in a monochorionic diamniotic twin pregnancy put on evidence by color Doppler. The typical biphasic wave translating a bidirectional flow can be seen. (Courtesy of T. Loureiro.)
Intertwin Membrane Folding
At 15 to 17 weeks of gestation the disparity in amniotic fluid volume between the 2 amniotic sacs seems to cause membrane folding: if present, 28% of cases developed severe twin-to-twin transfusion syndrome and 72% developed mild twin-to-twin transfusion syndrome. In the cases with absent membrane folding, no cases of twin-to-twin transfusion syndrome were recorded (Figure 13-41).
Ultrasound scan showing membrane folding in a monochorionic diamniotic twin pregnancy that is the ultimate expression of unbalanced amniotic fluid volume between the 2 sacs.
Twin "Embolization" Syndrome
Twin embolization syndrome is a complication of MZ twinning after in utero demise of the co-twin. It was believed to result from the embolization of placental and fetal thromboplastins or from the direct embolization of necrotic fragments of the placenta from the dead fetus and disseminated intravascular coagulation, causing embolization or even an endarteritis.61 The emboli damages predominantly highly vascularized organs such as the brain and kidneys, but can affect almost all organ systems.
This older theory is now abandoned for most cases, and the current explanation is that the recipient damage results from the sudden hypotension with the "drain back" of blood from the surviving twin to the low resistance territory of the dead fetus.19 The acute exsanguination of the surviving twin into the circulation of the dead twin through vascular anastomoses may cause irreversible brain damage in about 50% of the surviving co-twins and death in 38% of the cases. Cordocentesis performed in the survivor showed anemia within 24 hours after death. The results of coagulation screening tests on the surviving newborn twin at delivery are almost always normal. In the central nervous system (CNS), this brisk hypotension can result in ventriculomegaly, porencephaly, cerebral atrophy, cystic encephalomalacia, or microcephaly in about half of the cases.20,21 Extracranial abnormalities include small bowel atresia, gastroschisis, limb amputation, hydrothorax, aplasia cutis, and renal cortical necrosis.
The presence of any of the above-mentioned anomalies in the surviving twin with a dead co-twin should raise the suspicion. Only fetal death occurring during the second and third terms of pregnancy is considered.
Twin Reversed Arterial Perfusion Syndrome (or Acardiac Twin)
Twin reversed arterial perfusion (TRAP) sequence is a rare condition that has been reported at an incidence of 1% in monochorionic twin pregnancies (0.3 per 10,000 births), resulting in coexistence of a normal "pump" twin and an acardiac twin.62
The pathognomonic feature is the presence of reversed arterial perfusion on Doppler (Figure 13-42).62 When imaging the umbilical cord with Doppler, arterial waveforms are observed from the placenta toward the acardiac twin. Venous blood flow goes in the opposite direction.63 This finding results from the absence of a heart (pump) in the acardiac twin in association with artery-to-artery communications in the placenta, allowing the acardiac twin to get its blood supply from the normal twin.64
In twin reversed arterial perfusion syndrome, the "acardiac" twin is perfused retrogradely with poorly oxygenated blood that should have gone to the placenta.
The abnormal fetus presents with impaired or absent development of cephalic pole, heart, upper limbs, and many viscera (Figures 13-43 and 13-44). The lower limbs are relatively well preserved, although clubbing and abnormal toes are common. A 2-vessel cord is the rule (66%). The membrane development between the twins is inconsistent and varies from full sac to strips of membrane. Occasionally, the umbilical artery of the acardiac twin connects to the superior mesenteric artery (instead of the iliac artery), which is the persistence of a "primitive" vitelline supply.
This large mass is an acardiac twin (large cystic hygroma on the left), and there are poorly defined body parts on the right.
Two sets of acardiac twins demonstrate the range of development (A) (or absence of development, B) of the cephalic end.
The mechanism that has been proposed is the association of paired artery-to-artery and vein-to-vein anastomoses through the placenta combined with delayed cardiac function of one of the twins early in pregnancy. Some investigators have also suggested that aneuploidies, which could lead the abnormal twin to have a slower development than the healthy twin, could be a possible etiological factor. Chromosomal abnormalities have been found in one-third of acardiac twins. If one twin develops more slowly, the imbalance in the blood pressure of the twins will result in a retrograde transfer of blood from the healthy twin to the abnormal twin. The retrograde flow of poorly oxygenated blood through the developing heart of the abnormal twin interferes with the development of that twin's heart, which rarely goes beyond the stage of tubular heart, causing the "acardia." The upper half of the body of an acardiac twin is extremely poorly developed and, sometimes, not developed at all. Although there are many appearances, head, cervical spine, and upper limbs are usually absent. Edema and sonolucent areas in the upper body, consistent with cystic hygroma, are common. In contrast, the lower half of the body, although malformed, is better developed. This pattern of development may be explained by the mechanism of perfusion of the acardiac twin. Blood that enters the abdomen of the fetus is deoxygenated blood coming from the normal twin (Figure 13-45). The morphologic abnormalities in the acardiac twin are consistent with perfusion of tissues supplied by the common iliac and lower branches of the aorta with deoxygenated blood. Most of the oxygen available is extracted when the blood enters the acardiac twin, allowing for some development of the lower body and extremities. Lower pressure in the retrogradely perfused upper half of the body and low oxygen saturation impair the development of this area.65,66
Reverse flow on pulsed color Doppler: arterial flow in the vessel goes in (under the baseline) and venous flow in the vessel goes out (above the baseline).
The acardiac twin is thus a parasite. It requires blood pumped from the normal twin to keep developing, putting the pump fetus at risk of high-output cardiac failure (Figure 13-46). The risk is directly dependent on the size of the acardiac twin: the heavier the acardiac twin, the greater the risk of cardiac failure and death for the normal twin. Overall only 50% of pump twins survive, and the mortality for acardius is 100%.
Drawing from the case reported by Highmore. (From Highmore N. Case of a fœtus found in the abdomen of a young man, at Sherborne, in Dorsetshire. R Coll Surg 1815.)
Management includes conservative and invasive therapies. Conservative management includes serial, ultrasonography, echocardiography, cardiotocography and opportune delivery. Noninvasive therapies may be used to support the cardiac function of the pump twin with digoxin and indomethacin. The more invasive management consists of termination of pregnancy or interruption of flow to the acardiac fetus; surgical extraction (hysterotomy with selective delivery of the acardiac twin) and ligation of the acardiac twin's umbilical cord67; ultrasound-guided embolization of the cardiac twin's umbilical artery with absolute alcohol, platinum coils, or thrombogenic coils; and laser vaporization. Large numbers are not available to compare the various techniques.
Few entities can resemble an acardiac twin. Occasionally, a twin-to-twin transfusion could resemble a TRAP. These entities can be differentiated by the recognition of a membrane (even in a stuck twin) and, of course, cardiac activity in the smaller fetus. A fetal demise in a twin pregnancy could also resemble acardius; however, there should be no Doppler signal in the dead fetus.
There are no associated syndromes.
A fetus in fetu is an encapsulated, pedunculated vertebrate tumor. It represents a malformed monozygotic, monochorionic, diamniotic, parasitic twin included in a host (or autosite) twin (see Etiology, below). Characteristically, the fetus-in-fetu complex will be composed of a fibrous membrane (equivalent to the chorioamniotic complex) that contains some fluid (equivalent to the amniotic fluid) and a fetus suspended by a cord or pedicle. The presence of a rudimentary spinal architecture is used to differentiate a fetus in fetu from a teratoma because teratomas are not supposed to develop through the primitive streak stage (12 to 15 days). This last criterion has been considered too stringent by many investigators who regarded rudimentary body architecture (metameric segmentation, craniocaudal and lateral differentiation, body coelom, and "gestational sac") or the presence of an associated fetus in fetu as equivalent criteria. Although teratomas can achieve striking degrees of differentiation by the inductive effect of adjacent tissues on one another, they do not present the criteria mentioned earlier.
Several cases of fetus in fetu were reported in the past, and no distinction from teratoma was made until the first quarter of the 20th century. For this reason, those reports that did not clearly identify the presence of a spine should be considered with caution. Further, because of possible confusion with abdominocyesis, cases in women of child-bearing age should be interpreted cautiously. One case reported by Highmore68 occurred in a teenaged boy (see Figure 13-47). This 15-year-old boy had a 7-year history of abdominal complaints and mass. As in the previous case, the child died of malnutrition. At autopsy, a large tumor containing a fetus was discovered.
Anastomoses between vitelline vessels are believed to cause the common form of fetus in fetu.
The prevalence is unknown. About 100 cases have been reported, but this number changes according to how strictly identification criteria are used. Several cases have been formally recognized by some as fetus in fetu but categorically rejected by others. Seven cases have been detected in utero. An estimated frequency of 0.02 per 10,000 births is commonly reported in the literature, but this number is based on the unsubstantiated assumption that fetus in fetu represents 5% of conjoined twins. Further (see Etiology), the current trend is to consider that fetus in fetu does not represent a form of conjoined twins. The male-to-female ratio in the 39 reports that we reviewed was 1.3 males to 1 female. This is in contrast to conjoined twin, which occurs predominantly in girls.
Only a few cases were detected prenatally and presented as a complex mass. The general appearance is a well-delineated capsule, with an echogenic mass suspended in fluid or partly surrounded by fluid. Occasionally, the diagnosis can be suggested by the recognition of a rudimentary spine (Figures 13-47 and 13-48).
A fetus in fetu with a rudimentary organization. (Courtesy of O. Brandão.)
As with any unusual anomaly, several descriptive terms have been used. These include cryptodidymus (κρıπτο = hidden, δıδυοζ = twin), dermocyme (δερμα = skin, κυμα = fetus), double monster, endocyme fetus (ενδον = inside, κυμα = fetus) (note that the word fetus is redundant), fetiform teratoma, fetal inclusion, included heteropagus twin (ετεροζ = other, παγοζ = which is fixed), and suppressed twin.
Several etiologies have been proposed. A primordial organizer defect was once thought to explain dermoids, teratoma, and embryoma.
Another theory suggested that the fetus in fetu derived from germ cells from the host that evolved on their own. This appears to be supported by the occasional localization in an ectopic testicle. However, that localization can also result from migration of the fetus in fetu along with the germ cells, when the germ cells of the host return from the yolk sac into the retroperitoneal cavity on their way to the gonads.
A parthenogenetic origin has also been suspected. In this theory, germ cells from the retroperitoneal region (where they normally are located) are parthenogenetically stimulated and evolve into a rudimentary fetus. Histocom-patibility studies and gene markers do not support parthenogenesis as a likely etiology.
In the continuum theory of monozygous twin, there is a progression from normal twins to conjoined symmetrical twins to asymmetrical twins (acardiac twins), and then to parasitic twins, and then teratoma is hypothesized. The incidence is about equally divided between sexes (with a slight male predominance in this review), which is an argument against the continuum theory and the highly differentiated sacrococcygeal teratoma theory because conjoined twins and sacrococcygeal teratomas are more common in females.
Some authors suggest considered that the fetus in fetu did not represent a monoamniotic twin but rather included a monozygotic diamniotic parasitic twin within the host twin: "It is, I believe, a mistake to suppose that a gentle series of gradations exists between double monsters and malformed twins on one hand and teratomas on the other—a mistake widely promulgated because of the prevalent view that teratomas are included monsters or malformed twins. The sooner this misconception is abandoned, the better." His postulate explains why in all extracranial locations the fetus in fetu is embedded in a gestational sac. If the fetus in fetu were a conjoined twin, it would have to be monoamniotic and thus would not have its own gestational sac. This theory has been widely accepted.69
The currently accepted mechanism is the embedding of a twin due to vitelline circulation anastomoses. Vascular anastomoses between twins have variable repercussions, depending on the vessels anastomosed and the location of the anastomoses. The most benign anastomoses are superficial connections of similar vessels on the surface of the placenta. These connections between artery and artery or between vein and vein are common and of limited significance when they occur after the first few weeks of gestation. When they occur early and one fetus has a slight developmental delay, they result in the TRAP syndrome. Anastomoses that are between dissimilar vessels and occur in the placenta are responsible for the twin-to-twin transfusion syndrome.
Anastomoses between vitelline vessels, which are only possible when the twins are monochorionic, are assumed to cause fetus in fetu by a mechanism similar to that which produces acardiac twins. The cardiac development of the affected twin is impaired by the reversal of the flow in its heart. This stunts the growth of the affected fetus, and as the host grows it progressively embeds the smaller twin around the third week.
A few intracranial cases have been described. The location in the skull results from a different embryologic mechanism. To be imbedded in the ventricle, a fetus in fetu has to separate at a much later date than those that are imbedded in the retroperitoneum. At 15 days, when the embryo is at the bilaminar disk level, the primitive streak develops. At the cephalic end of the streak, a depression, the primitive knot or Hensen node, forms and extends cranially. The invagination of the cells into the depression is at the origin of the mesoderm and forms the notochordal process (or blastopore). The blastopore extends to become the notochord, which elongates toward the cranial end. If a second differentiation focus occurs in the bilaminar embryo and grows at the same rate as the primary focus, it will form a craniopagus conjoined twin. If the second differentiation focus grows more slowly than the primary focus, it will be engulfed in the invagination of cells and may arrest in what will ultimately become the ventricles. A fetus in fetu thus may also settle along the central canal of the spinal cord. In intracranial fetus in fetu, one does not expect to find a gestational sac (amnion or chorion equivalent), and indeed none of the intracranial cases have described any surrounding membranes (Figures 13-48 and 13-49).
Most cases of fetus in fetu are retroperitoneal, but some have been found in the mesentery, adrenal cranial cavity, lateral ventricles, pelvis, coccyx, inguinal region, testicles, and scrotum. Thus, most of the resting places are retroperitoneal or on the path that the germ cells follow on their way back from the yolk sac to the retroperitoneum and into the gonads. When located on ectopic testes, they may be intraperitoneal. The affected testicle is usually ectopic or undescended, probably because the added bulk impairs the migration of the cells.
As expected from the etiologies, most cases of fetus in fetu are connected to the host by vessels originating from or around the superior mesenteric artery, a derivative of the right vitelline artery in mammals. The artery of the fetus in fetu derives from the vitelline artery and thus is the equivalent of a superior mesenteric artery. In the host, if the superior mesenteric artery is not directly involved, the connection is usually with direct branches from the aorta and the small retroperitoneal or diaphragmatic vessels. In a testicular location, spermatic vessels or even renal and adrenal vessels may be involved. In only a few cases, a definite vascular connection can be recognized between the fetus in fetu and the host. In other cases, a capillary system exists between the 2 circulations. Because the fetus in fetu does not have a cardiac system, the severe hypoxia is responsible for the lack of evolution.
Only a few cases have been detected prenatally. Most cases are discovered in newborns or small children.
The weight varies from a few grams to 2000 or even 4000 g. There is some inexactitude in the reporting of the weights because some reports mention the weight of the whole tumor and others report the weight of the fetus in fetu alone.
Presenting Symptoms in Children
Aside from a few fortuitous discoveries, the disorder usually becomes apparent from its compression of adjacent organs, principally the gastrointestinal tract.
Usually 1 fetus is found, but several instances of 2, 3, 5, or even more have been described. When several fetuses are present, they usually share the same sac, but some may have their own sacs.
Studies of gonads, blood types, chromosomes, and red cell antigens (ABO, Rh, M, N, S, P1, K, Fy, and Jk) have shown the fetus in fetu to be monozygotic to the host. It is not surprising, however, that the fetus in fetu has the same blood type as the host because it is perfused by the host. There have been no recorded cases of dizygosity. However, as in acardiac twins, the combination of a normal twin with a twin that has lost a gonosomic chromosome and thus appears as a 45,X0 could potentially be found.
At surgery, the fetus in fetu appears as a well-circumscribed mass bound by a fibrous membrane. Inside the mass the fetus in fetu is suspended in straw-colored fluid by a pedicle. Two vessels (an artery and a vein) travel along the pedicle. The fluid is generally not abundant and has been described as containing sebaceous material. The origin of this fluid is uncertain. Several investigators have pointed out that the membranes of a normal embryo are not responsible for the production of amniotic fluid. They would more likely act as a semipermeable membrane. In fetuses past 12 weeks, the urinary system produces the fluid and the gastrointestinal system reabsorbs it. Because no fetus in fetu has ever been described to contain a urinary system and the segments of gastrointestinal tract that are found are too incomplete to have any reabsorptive capabilities, the fluid is probably in communication with the extracellular fluid of the fetus in fetu and is maintained in the amniotic cavity solely by osmotic and oncotic pressure.
The presence of chorionic villi has only been reported in 1 case. Except for 1 quotation of a 15 year old saying, "Mother, do come to me, I have something alive in my body," and the mother being quoted as saying that she felt something resembling "the motion of a child during gestation," no fetal movements have ever been recorded in a fetus in fetu. This record of movement is somewhat doubtful because striated muscles have rarely been found around joints. Yet this host is one of the older hosts described.
Fetus in fetu resembles poorly formed acardiac twins. Almost every organ has been recognized in various stages of development. The notable exception is the urinary tract, which does not appear to have been recognized in any of the cases that we reviewed. Some structures such as ribs, intrathoracic organs (lung, heart, and thymus), and retroperitoneal organs (liver, spleen, kidneys, adrenal glands, pancreas, and gonads) are rarely described. An incomplete heart has been found. In 1 instance, a rudimentary 2-chamber heart was found, with the atrium in the caudal position and the ventricle in the cranial position. This is the stage normally reached in a 22-day embryo. Facial and cranial structures also are seldom seen, yet eyes, ears, mouth, and poorly organized brain and cerebellum have been observed.
The cord that connects the fetus to the membrane has different characteristics than a normal cord: it contains vasa vasorum and nerve fibers.
The evolution of the fetus in fetu is usually arrested at the first trimester, and further evolution is by mass accretion more than by development. Overall structures derived from the ectoderm are better represented than structures derived from the other 2 layers. The mesoderm contributes the musculoskeletal system, which is usually well represented, but the other derivatives (the vascular and urogenital system, the spleen, and adrenal glands) are seldom found. The most commonly represented derivative from the endodermal layer is the gastrointestinal tract, but the liver and pancreas are also often recognized.
When discovered in a newborn child during physical examination, the differential diagnosis includes all the common masses such as Wilms tumor, hydronephrosis, and neuroblastomas. Prenatally, the main differential diagnosis is with teratoma. Teratomas are disorganized congregations of pluripotential cells from all 3 primitive tissue layers. By differentiation and induction, they can achieve striking organization, with examples of several organs being well formed. However, teratomas do not have vertebral segmentation, craniocaudal and lateral differentiation, body coelom, or systemic organogenesis. Thus, the presence of a mass with a spinal organization and surrounded by fluid suggests the correct diagnosis. When spinal structures are not present, most investigators have considered that the diagnosis of fetus in fetu can still be made. These criteria are sufficiently restrictive that even well-organized teratomas cannot fulfill all of them. Teratomas have a definite malignant potential, a feature that has not been reported in fetus in fetu. Teratomas occur predominantly in the lower abdomen, not in the upper retroperitoneum. Nonetheless, the coexistence of a fetus in fetu and a teratoma and the occurrence of a teratoma 14 years after removal of a twin fetus in fetu have been reported, thus supporting the older hypothesis of a continuum between twin and teratoma. Cases of sacrococcygeal fetus in fetu should probably be regarded and treated as teratoma because of the high incidence of teratoma in this region.
Ectopic testicles have a higher incidence of germ cell tumors, and the differentiation between fetus in fetu and teratoma is particularly important. Although the characteristics of intracranial teratoma differ from those of intracranial fetus in fetu, Wakai et al found, in a large review of intracranial teratomas, that there are some transitions between certain teratomas and fetus in fetu.
Every organ of the fetus in fetu has undergone hypoxic growth and is deformed. Most cases are anencephalic. Usually the body is closed, but ventral wall defects such as omphalocele are common, and a case that suggests a limb–body wall complex has also been described. The host rarely presents any anomalies, except those related to the presence of a space-occupying lesion. Those manifestations have rarely been severe, even in the case of intracranial fetus in fetu, although in rare cases severe hydrocephalus was responsible for the death of the host. One case of Meckel diverticulum and another of skin hemangioma have been described. A malignant degeneration has never been reported, even in the cases that have been allowed to evolve for several years.
If conservative management is chosen, the fetus in fetu does not seem to be harmful to the host. However, in every case in which the fetal mass was not removed at the time of discovery, a slow growth has been described.
In the literature of the 19th century, fetus in fetu was fatal to the host because of the compression on adjacent organs. In the more recent literature, the outcome for the host twin is usually favorable. Only a few cases of spontaneous or postsurgical deaths have been recorded.
There is no report of recurrence.
Aside from a few attempts, in the first half of the 20th century, to marsupialize the fetus in fetu, surgical removal is the treatment of choice. The membranous capsule can usually be enucleated from the host with minimal problems. In only a few cases, removal is difficult because of adhesions, and this difficulty may precipitate the end of the operation or even be the reason for the postoperative death of the host. Leaving the capsule, or part of it, has not led to complications except in very rare cases in which fluid reaccumulated in it.