Section 6 -

Multiple Gestation Phyllis C. Huettner, M.D.

Multiple gestation has always been an unusual and therefore fascinating occurrence. From a medical point of view, twin and higher order multiple gestations are associated with much higher rates of mortality and morbidity compared to singleton gestations. Twins account for 12.6% of perinatal mortality even though they make up only 2.5% of the population. Some forms of morbidity that are more common in multiple gestation, such as low birth weight, anomalies, malformations and cerebral palsy, can be seen in any type of gestation, whereas other complications, such as twin-twin transfusion syndrome, occur only in multiple gestations where vascular anastomoses in the placenta result in shared circulation between the twins. Despite the increased incidence of twinning with the widespread use of assisted reproductive technologies and our appreciation of the complications to which they are prone, there are no prospective, randomized studies that address the important issue of how to optimally follow twin pregnancies for complications throughout gestation. Twins make up about 1 in 90 pregnancies but this figure may not be precise because some gestations thought to be twins in the early first trimester will be singleton gestations by the end of the second trimester. Assisted reproductive technologies (ART) have resulted in a dramatic increase in multiple gestations, particularly triplets and higher order multiples. It is estimated that today about 50% of twins are conceived through ART. About 70% of twins are dizygous (fraternal) resulting from the fertilization of two ova. About 30% of twins are monozygous (identical) resulting from the fertilization of a single ovum that splits very early in gestation. The rates of monozygous twinning are constant whereas the rates of dizygous twinning vary widely among different populations reflecting a genetic tendency to ovulate more than one ovum. The complications that twins experience are not related so much to whether they are monozygous or dizygous, but more specifically to the type of placentation they have. All dizygous twins exhibit diamniotic dichorionic placentation. Monozygous twins, on the other hand, may exhibit any type of placentation. About 25% are also diamniotic dichorionic but 75% are monochorionic (MC). The type of placentation seen in monozygous twins is determined by when in gestation the split occurs. If division occurs before 4 days post fertilization diamniotic dichorionic (DC) placentation will result. If division occurs between 4 and 8 days post fertilization diamniotic MC placentation will result. If division occurs after 8 days post-fertilization monoamniotic placentation, sharing a single sac with no dividing membranes, results. If division occurs after 13 days post fertilization the twin fetuses will be conjoined. From a practical point of view, dichorionic placentas can be seen in dizygous or in monozygous twins but monochorionic placentas only occur in monozygous twins. However, a recent report by Souter et al and further explained in an accompanying editorial by Redline, illustrate a case of dizygous twins, male and female, with monochorionic placentation. These twins were conceived through ART. So while monochorionic placentas are almost always associated with monozygous twins, very rarely twins conceived through ART could have a monochorionic placenta but be dizygotic if the developing conceptus fuses or aggregates abnormally very early in development. Diamniotic DC placentas have two separate sacs separated by dividing membranes that are thick and opaque. The placental parenchyma may be separate or fused. During examination, it is important to note the relative proportions of total placental parenchyma associated with each sac. Microscopic sections of the dividing membranes show fused amnion and chorion. The vessels of the two twin territories may approach the dividing membranes but they do not cross. With very rare exceptions, no vascular anastomoses are seen in DC placentation. In diamniotic MC placentas, the dividing membranes are very thin and translucent. Microscopically one sees fused amnion with no chorion. The vessels of diamnionitic MC placentas show anastomoses in 85% to 100% of cases. The anastomoses may involve the surface vessels or deeper vessels within the parenchyma. Injection studies to demonstrate vascular anastomoses should be performed in all monochorionic placentas. These studies must be performed on fresh placentas. This is discussed in more detail under twin-twin transfusion. Prenatal ultrasound is able to correctly diagnose about 91% of MC twins and 96% of DC twins by measuring the thickness of the dividing membranes. This is most accurately done in the first trimester. The chorionicity of multiple gestations of higher order should be determined in the same way. For example the dividing membranes between A and B, B and C and A and C should be examined in triplets. The complication rate for twins is highly related to the type of placentation and is much higher for most complications in MC twins. MC twins have a 12.2% fetal loss rate before 24 weeks gestation compared to just 1.8% for DC twins. The perinatal mortality rate for MC twins is 2.8% and for DC twins is 1.6%. About 9.2% of MC twins are delivered before 32 weeks compared to 5.6% of DC twins. Low birth weight (<5th percentile) in both twins complicates 7.5% of MC twin gestations but only 1.7% of DC gestations. Interestingly there is little difference in the percentage of twin pairs with discordant growth (about 12%) in DC and MC gestations, emphasizing that not all discordant growth is due to the TTTS or vascular anastomoses, both of which only occur in MC twins. Monoamniotic twins have an even higher rate of complications than MC twins with a mortality rate between 28% and 70% due largely to prematurity and cord accidents in these twins that share an amniotic sac. Case 7: Twin-Twin Transfusion Syndrome (TTTS) TTTS is a devastating condition that occurs in about 15% of MC twins. It is the result of a chronic imbalance of blood flow across the two placental circulations. One twin, referred to as the donor, supplies the blood for both twins resulting in hypovolemia, oliguria and oligohydramnios in this twin. The other twin is the recipient of this extra blood flow and experiences circulatory overload resulting in polyuria, polyhydramnios and eventually hydrops fetalis. Often, but not always, the twins are discrepant in size. The pathophysiology of TTTS is complex but always involves vascular anastomoses between the two circulations. Vascular anastomoses can be artery to artery (A-A), vein to vein (V-V) or artery to vein (A-V). A-A and V-V anastomoses are usually superficial and bidirectional. More important physiologically are A-V anastomoses. These are present at the capillary level and therefore are deep in the parenchyma, not visible on gross examination. These allow blood to flow in only one direction and therefore can result in a chronic imbalance of the blood flow. One important clue to the presence of A-V anastomoses is the presence of a superficial artery or vein without a pair on the surface of the other twin. A recent study has demonstrated, however, that a high percentage of MC twins have deep A-V anastomoses without an unpaired superficial artery or vein to serve as a clue to its presence. Anastomoses can be demonstrated by injecting air, milk or water into a vessel in one twin's circulation and observing whether the material appears in vessels in the other twin's circulation and in which type of vessels. These injection studies must be performed before fixation of the placenta. A recent study has reported the use of color-coded gelatin-dye mixtures which have the advantage of remaining in tissue after sectioning allowing determination of the size of vessels involved in anastomoses. Certain types of vascular anastomoses may be protective. For example, TTTS is present in 58% of twins without A-A anastomoses but only 5% of cases with A-A anastomoses. It is thought that these large superficial A-A anastomoses may help "balance out" the circulation and protect against TTTS. Other factors besides vascular anastomoses may determine whether TTTS will develop and how severe it will be. Velamentous cord insertion is more common in twins with TTTS, especially in the donor twin. It is thought that compression of the intramembranous vessels by amniotic fluid in these cases may contribute to the circulatory imbalance. Dysfunction in the placenta of one twin, such as extensive infarction, may increase the resistance in that part of the circulation, and also contribute to vascular imbalance. The mortality rate from TTTS, if untreated, is 90%. Both twins are at risk. If only one twin dies it is usually the donor. The donor twin may be anemic or hypoglycemic while the recipient twin may develop heart failure, hemolytic jaundice, thrombosis from secondary hemoconcentration or kernictuerus. In fatal cases, the organs of the donor are usually small, pale, and anemic while those of the recipient are heavy and congested. There may be acute shifts in blood flow at the time of delivery, however, that may alter the appearances of the infants and their organs such that the donor may appear plethoric and the recipient may be pale and anemic. Similarly, death of one twin may resolve the TTTS but may also decrease the resistance in that portion of the placenta causing the live twin to exsanguinate into the relaxed territory of the dead twin. The placentas also usually have markedly different pathologic features as well. The placenta associated with the donor is typically large, bulky and pale with large, edematous villi and increased nucleated red blood cells. There may be amnion nodosum related to oligohydramnios in this twin. The placenta associated with the recipient, on the other hand, is typically small, firm and congested. Treatment options for TTTS are controversial. If the twins are sufficiently mature, delivery is the best option. Amnioreduction, to balance the volume of amniotic fluid between the twins is effective in only mild cases and is associated with a 50% mortality in one or both twins and a 16% rate of severe neurologic abnormalities. Rupture of the dividing membranes has no proven efficacy. Laser coagulation of the anastomotic vessels of the chorionic plate has proven effective even in advanced cases and is associated with an overall survival of 71% and only an 8% rate of major neurologic sequelae. De Paepe et al have recently described their experience with placental findings after laser ablation. The coagulated vessels show an abrupt interruption in the flow of dye or other injected materials. In cases laser coagulated less than a month before delivery, there will be vascular hemorrhage. If more than a month has lapsed since laser coagulation, the absence of anastomoses will be obvious with an area of increased subchorionic fibrin between the two vascular territories. Organizing thrombi, hemosiderin and avascular villi were also observed. Discordant Development Interestingly many major, lethal anomalies are discordant even in MC twins. About 12% of twins, both DC and MC, will have a greater than 25% difference in fetal weight. Discrepant weight has a greater mortality rate in MC twins. Causes of discrepant growth include the inequalities in placental sharing, the quality of implantation in each of the territories and the details of the angioarchitecture. The type of umbilical cord insertion may also be important. When only one of a pair of MC twins has a velamentous cord insertion, about half have discordant fetal growth. Discrepant fetal growth is not a complication in DC twins when only one umbilical cord is velamentously inserted. Selective termination may be used to treat severe discrepancies in fetal growth, not related to TTTS in cases of DC twins, but this therapy cannot be applied to MC twins because vascular anastomoses between the placental circulations puts the remaining fetus at risk. Acardiac Twin Acardiac twinning represents a special form of discordant growth. It complicates about 1% of MC twins. In this condition a second, grossly malformed twin is attached by an umbilical cord to the placenta. Some of the acardiac twins are amorphous blobs of tissue whereas others show a remarkable degree of development, lower extremities more so than upper extremities. All of these twins lack a functioning heart. Usually the cord to the acardiac twin has a single umbilical artery. An A-A anastomosis in the umbilical cord or in the vessels of the chorionic plate promote blood flow from the normal twin to the acardiac twin. The blood flows in reverse in the acardiac and returns to the pump twin by a V-V anastomosis. There are two main theories of pathogenesis. One is that the reverse flow is caused by regression of the heart in one twin. The other theory is that acardiac twinning only occurs in those special cases of MC twins in which the specific A-A and V-V that allow for this reversal of flow are present. The acardiac twin is never sufficiently developed to allow for independant survival after birth. The pump twin is at increased risk of cardiac failure and preterm delivery. Intrauterine Death of One Twin As in TTTS when one twin dies, the vascular system of the dead twin loses its resistance and the live twin may exsanguinate into the relaxed vasculature of the dead twin. This situation is associated with significant morbidity in the surviving twin that is thought to be related to sudden hypotension and hypoperfusion of the organs rather than thrombi or embolization into the vessels of the survivor. It has recently been suggested that the injuries in the survivor are related to the sudden changes in the placental territory that is now perfused by the live twin. Placental examination is helpful in documenting and timing an intrauterine death. When one twin dies weeks earlier than the other, the territory of the dead twin may be much thinner and paler than that of the live twin. When one twin dies early in gestation, the mummified remnant of the fetus may be present in the placenta. This is called a fetus papyraceous. Often the compressed gestational sac and atretic umbilical cord can also be identified. It is particularly important to look for this in cases of ART, especially when it was known that more than one fetus was present early in gestation. References: Bermudez C. et al. Placental types and twin-twin transfusion syndrome Am J Obstet Gynecol 2002;187:489-494. Cleary-Goldman J and D'alton M. Management of single fetal demise in a multiple gestation. Obstet Gynecol Survey 2004;59:285-298. De Paepe ME et al. Demonstration of placenta vascular anatomy in monochorionic twin gestations Pediatr Dev Pathol 2002;5:37-44. De Paepe ME et al. Placental findings after laser ablation of communicating vessels in twin-to-twin transfusion syndrome. Ped Devel Pathol 2004;7:159-65. Feldstein VA and Filly RA. Complications of monochorionic twins. Radiol Clin N Am 2003;41:709-727. Fries MH et al. The role of velamentous cord insertion in the etiology of twin-twin transfusion syndrome. Obstet Gynecol 1993;81:569-574. Gersell DJ and Kraus FT. (2002). In: RJ Kurman ed., Blaustein's Pathology of the Female Genital Tract, 5th ed. New York: Springer-Verlag, p. 1119-1133 Giminez-Scherer JA and Davies BR. Malformations in acardiac twins are consistent with reversed blood flow: liver as a clue to their pathogenesis. Pediatr Dev Pathol 2003;6:520-530. Huber A, Hecher K. How can we diagnose and manage twin-twin transfusion syndrome? Best Pract and Res Clin Obstet Gynecol 2004;18:543-56. Lewi L et al. Monochorionic diamniotic twins: complications and management options. Cur Opin Obstet Gyncol 2003;15:177- 194. Machin GA. Velamentous cord insertion in monochorionic twin gestation: an added risk factor. J Repro Med 1997;42:785-789. Machin GA. Why is it important to diagnose chorionicity and how do we do it? Best Prac Res Clin Obstet Gynecol 2004;18:515-530. Redline RW, et al. Placental lesions associated with abnormal growth in twins. Pediatr Dev Pathol 2001; 4:473-481. Redline RW. Nonidentical twins with a single placenta-disproving dogma in perinatal pathology. [comment]. New Engl J Med 2003;349:111-114. Robertson EG and Neer DJ. Placental injection studies in twin gestation. Obstet Gynecol 1983;147:170-174. Shere DM. Adverse perinatal outcome of twin pregnancies according to chorionicity: review of the literature. Am J Perinatol 2001;18:23-37. Souter VL et al. A report of dizygous monochorionic twins. New Engl J Med 2003;349:154-158. Victoria A et al. Perinatal outcome, placental pathology, and severity of discordance in monochorionic and dichorionic twins Obstet Gynecol 2001;97:310-15. Wen SW et al . Maternal morbidity and obstetric complications in triplet pregnancies and quadruplet and higher-order multiple pregnancies. Am J Obstet Gynecol 2004;191:254-258.