Chapter 13: SONOGRAPHY IN MULTIPLE GESTATION

Multiple pregnancies represent about 1.2% of all pregnancies. Large regional and racial differences with up to 15-fold variation in the prevalence of twinning at birth have been noted for many years (Figure 13-1). Environmental and dietary factors, seasonality, and family clustering considerably influence the twinning rate.

In Western countries about 30% of these pregnancies are iatrogenic (in a hypothetical obstetric population of 10,000 newborns, 84 spontaneous twins and 36 resulting from assisted reproduction), from which 27 twins would be spontaneously monozygotic and 2 iatrogenic.¹ Increased use of ovulation induction and assisted reproduction techniques (ART), coupled with delay in the reproductive age of pregnant women, have contributed to an increase in multiple pregnancies.^{1,2, and 3} These iatrogenic pregnancies contributed not only to the increase in the rate of dizygotic (DZ) twins but also of monozygotic (MZ) twin pregnancies.^2,3 In iatrogenic pregnancies the ratio is altered and MZ twin pregnancies are more prevalent (6-fold increase).^{2,3,4, and 5}

The growing concern with multiple pregnancies is their higher mortality and greater incidence of adverse perinatal outcome compared to singleton pregnancies,⁶ to the doubling of risk for structural defects^7,8 and to the higher risk of chromosomal anomalies.⁹ Although multiple pregnancies represent 1.2% of the population, they contribute to 10% to 14% of the overall perinatal mortality, a rate 5 to 10 times higher than that of singletons (Figure 13-2A and B).⁶ The perinatal mortality of monochorionic twins is 26 per 100, which remains 3 to 5 times higher than in dichorionic (DC) pregnancies (9 per 100). The rate of perinatal loss before 24 weeks in monochorionic compared with DC pregnancies is 12.2% versus 1.8%.⁶

The aim of early diagnosis of multiple gestations and their associated complications is the reduction of perinatal morbidity and mortality. Sonography allows determination of the number of fetuses, amnionicity, chorionicity, placental location, fetal presentation, and the detection of complications such as growth discrepancy, abnormal vascular anastomoses, amniotic fluid volume imbalance, fetal malformations, and cord entanglement. In this chapter, we discuss the different aspects of ultrasonographic evaluation, the most common complications, and the role of invasive procedures in the management of multiple pregnancies.

The typical human cycle produces only one egg. Therefore, in about 99% of spontaneous pregnancies, a unique fetus derives from a single zygote. As a consequence of a reproductive variant, which occurs in 0.8% of spontaneous conceptions, more than one oocyte is produced and fertilized in each cycle, resulting in a polyzygotic multiple pregnancy. This type of twinning results in genetically different individuals (also known as polyzygotic, nonidentical, or fraternal twins) and has a hereditary tendency. It is associated with a recurrence risk 3 times higher than that of the general population. Each zygote develops its fetal–placental–amniotic compartment, and there are no (or are very rare) vascular communications between them.

In another 0.4% of spontaneous pregnancies, as a result of a reproductive anomaly, a single ovum normally destined to produce a single embryo splits to form MZ multiples. The MZ twinning is a form of reproduction whereby more than one individual results from a single zygote.

Why does the division of a single zygote occur? Presently, 4 theories are available to explain the mechanism of zygotic splitting: the repulsion hypothesis, the existence of co-dominant axes, depressed calcium levels in the early embryo, and the blastomere herniation hypothesis through a gap in the zona pellucida. All these theories are, however, not convincingly clear to explain the origin of MZ triplets and quadruplets, and do not clarify the higher rate of MZ twins related to ART techniques. More recently the hypothesis that human fertilized oocytes more splitting-prone are able to undergo 1 or 2 successive binary fissions,¹⁰ or various combinations offered by subsequent secondary fissions, just as in the case for the 9-banded armadillo, and give rise to a variety of combinations of MZ pregnancies (Figure 13-3). This latter theory would be able to explain MZ triplets and quadruplets, and "mirror-image" characteristics, as well as some midline asymmetries in MZ twins.

The timing of MZ twinning events can be inferred from the type of placentation, X chromosome inactivation in female MZ twins, asymmetric language function in the cerebral hemispheres, and asymmetric dermatoglyphs.

Dizygotic twins, fraternal or nonidentical, result from the fertilization of 2 ova by different spermatozoids, resulting in different genetic contents. The type of placenta resulting from this process of fertilization, in which the trophoblast formation precedes the egg implantation, has 2 chorions and 2 amniotic sacs, defining a dichorionic diamniotic pregnancy. Hence, DZ twins always yield dichorionic placentas.

Monozygotic twins comprise one-third of all twin pregnancies. These identical or uniovular twins result from the early division of a single egg (originating from the fertilization of an oocyte and a single spermatozoid) into 2 more or less identical cell masses that contain the same genotype (exception: heterokaryotypic monozygotes). This cleavage will occur between the fertilization and the gastrulation period (Figure 13-4). Individual variations are the result of post-zygotic mutations and arbitrary division of mitochondrial DNA. The placentation process inherent to these twins is more complex, depending on the very moment in which the separation occurs. Less frequently, MZ and DZ twinning may occur simultaneously in a pregnancy with 3 or more embryos (Figure 13-5).

In about one-third of naturally conceived MZ twins, the division will occur during the first 72 hours postconception (during the 2- to 8-cell stage), resulting in a dichorionic diamniotic pregnancy (Figure 13-6). Each twin receives trophoblastic and somatic stem cells into their cell masses. Therefore, twinning must have happened before the differentiation and physical separation of somatic and trophoblastic cells into the outer and inner cell masses, respectively, in the cavitated blastocyst at about 3 days postconception. Dichorionic diamniotic placentas are derived from the splitting of about 8 blastomers.

Splitting at any time thereafter results in a single monochorionic placenta that continues as such even in the face of subsequent MZ twinning in the inner cell mass. About two-thirds of MZ twins will develop a monochorionic diamniotic placentation as the result of the division of the embryonic cell mass between the third and the eighth day postconception (Figure 13-6). Two fetuses will develop with the same genome, a single placenta, and 2 amniotic cavities. The sharing of a single placenta is in itself an anomaly, creating the possibility of unequal vascular territories for each twin and the eccentric location of the umbilical cords. Eventually 5% to 15% will develop a twin-to-twin transfusion syndrome, and a discrepancy in fetal growth can be a frequent finding. Therefore, MZ twins may have either a dichorionic or monochorionic placentation.

If the division occurs between the 9th and 12th day, a single placenta and a unique amniotic cavity will be formed, that is, all placental structures will be shared, resulting in a monochorionic monoamniotic twin pregnancy (1%) (see Figure 13-6). The highest level of sharing occurs rarely when the division happens around the 13th day, producing conjoined twins (estimated prevalence of 1 in 100,000). Although commonly accepted as a term, "conjoined twins" is a misnomer. The anomaly results from an incomplete division, not fusion. Although Dr Spencer has argued in her text Conjoined Twins that the fetuses are fused, the cases of proven fusion are extraordinarily rare, and her hypothesis has been largely rejected by the peer-review process. After that time the undivided egg will maintain the expected course to produce a singleton. The different types of twins are listed in Table 13-1 (further details are in the text). The table is organized from the most dissimilar on top to the most similar at the bottom (see Figures 13-6 and 13-8).

If MZ twinning events would take place at a constant rate during the first 12 days postconception, proportions of dichorionic, monochorionic diamniotic, and monochorionic monoamniotic twins would vary from those observed. The under-representation at birth of monochorionic monoamniotic and conjoined twins is explained by a higher intrauterine lethality of the later stages of division. The relative excess of DC-MZ twins may be the result of their having fewer placental complications. The level of placental sharing is inversely proportional to the incidence of twins that result from this sharing—the incidence of MZ twins is about 1:250; the incidence of monochorionic twins is two-thirds of the MZ pregnancies (1:350 to 400 births); the incidence of monochorionic monoamniotic twins is 1:2500 liveborns; and the one from conjoined twins is fewer than 1:40,000 liveborns. On the other hand, perinatal mortality and morbidity are related directly with the level of sharing, that is, the greater the level of sharing the greater the risk of adverse pregnancy outcome (Figure 13-9). Whereas monozygotic with dichorionic placentation and DZ twins present pregnancies with similar risks, those with monochorionic placentation have an important increase in worse outcome, mainly if the shared circulation is unbalanced or if there are monoamniotic or conjoined twins.

In rare cases, a heterotopic pregnancy, which is the occurrence of a multiple pregnancy in which one or more gestational sacs are implanted outside the uterine cavity (ectopic pregnancy) along with a single or multiple intrauterine pregnancy (eutopic pregnancy), can occur. It can happen in 1% of pregnancies, more frequently after in vitro fertilization and embryo transfer.¹¹

During the ultrasound scan, one or more intrauterine gestational sacs are visualized with one or more ectopic pregnancies, which are classified depending on the site of implantation: tubal, cervical, cornual, abdominal, or ovarian.

The diagnosis can be made by transvaginal ultrasound during the first trimester. This diagnosis should be considered in cases of abdominal pain (vaginal bleeding may be absent) and in those with a failed pregnancy with rising human chorionic gonadotropin (β-hCG).

Differential Diagnosis

The presence of a small pelvic mass associated with an early intrauterine pregnancy is suggestive of a heterotopic pregnancy. The differential diagnosis can be made by the identification of the heartbeat. Patients with diagnosis of ectopic pregnancy, in particular the ones who have undergone infertility treatment, must have the uterine cavity investigated to exclude heterotopic pregnancy. The presence of an intrauterine gestation sac in a patient without symptoms should not exclude the diagnosis of a concomitant extrauterine pregnancy until the pelvis is carefully visualized. Heterotopic pregnancies can occur even in patients without risk factors.

Twin pregnancies that include a complete hydatidiform mole and coexisting fetus have a greater malignant potential. These extremely rare conditions should be differentiated from simple partial hydatidiform moles.¹²

It is chorionicity rather than zygosity that determines several aspects of antenatal management and perinatal outcome (Figures 13.2B and 13.9) The determination of the number of viable fetuses is also important since higher-order multiple fetuses have a greater risk of prematurity. The routine assignment of chorionicity and the earliest possible diagnosis of monochorionic twinning are desirable, though seldom achieved in practice.

Zygosity refers to the type of conception, whereas chorionicity denotes the type of placentation. The type of placentation depends on the time of splitting of the fertilized ova. A recent study suggests the possibility of determining zygosity, by means of ultrasound, in the beginning of the first trimester by counting the number of yolk sacs¹³; however, a unique placental mass and the same fetal sex suggest but do not prove monozygosity. It is not possible to determine zygosity in about 45% of cases because dyzigotic twins of the same sex (about half of the DZ twins) and monozygotic DC twins (one-third of all MZ twins) can not be differentiated unless molecular tests are used.

Shortly after the sixth postmenstrual week, heartbeats are visible and one can confidently count the number of embryos by the number of beating hearts. It is wise to wait until the eighth postmenstrual week to determine amnionicity. The amniotic membrane is so thin that it may remain inconspicuous until 8 to 9 weeks, leading to the incorrect consideration of a monochorionic monoamniotic gestation. In case of doubt, scanning the patient in lateral decubitus will often demonstrate the membrane: 1 of the 2 embryos appears "suspended" in the midst of the sac, resting on the yet nonvisible membrane.

When 2 embryos or fetuses assume a parallel, head-to-head position, conjoined twins should be suspected. A tap with the transducer should induce movements between the 2 fetuses, away from each other if they are separate or a global movement when the twins are conjoined. If a separating membrane is not identified it is important to look for sonographic signs of cord entanglement with the help of color Doppler.

At 10 to 14 weeks, the gold standard "window" for chorionicity definition, the chorion frondosum is sufficiently thick to be identified between the 2 layers of amnion as a wedge-shaped structure in a DC twin pregnancy (not necessarily a DZ twin pregnancy). This is the pathognomonic "lambda" (also occasionally called "twin peak" or "delta" sign) (Figure 13-10).^14,15 If a paper-thin (less than 2 mm), T-shaped septum without chorion interposed between the 2 amnions, along with like-sex twins, is found, a monochorionic twin pregnancy can be diagnosed (Figure 13-11).

After 16 weeks the chorion frondosum physiologically regresses and chorionicity assignment becomes less reliable (in the second trimester a false characterization of chorionicity can occur in 10% to 12% of cases).^15,16 The delta sign may be harder to identify¹⁷ and, if sexes are alike, monochorionicity can be wrongly inferred. It is the combination of several sonographic parameters that improves the diagnosis of chorionicity. Therefore, an adequate first-trimester scan of a multifetal pregnancy makes the subsequent second- and third-trimester evaluation more accurate, simpler, and faster.

If 2 separate placentas of different location, or 2 fetuses of a different sex or a thick interfetal membrane (>2 mm) with more than 2 layers, are found, dichorionicity should be suspected (Figure 13-10).¹⁸ Sixty-five percent of twins have the same sex; of these, 28% are monozygotic and 37% are dizygotic. Eighty percent of twins are diamniotic-dichorionic and that 90% of these diamniotic-dichorionic twins are also dizygotic. Further, 43% of same-sex twins are monozygotic.

The confirmation of a monochorionic placentation is only achievable by the detailed examination of the placenta. This exam includes the careful macroscopic examination of the placenta considering the number of placental masses, fetal and maternal surfaces of each placental disk, fusion of the chorion and amnion, thickness and translucency of the septum, and the vascular pattern of the fetal surface (Figures 13-12A and B).

Chorionicity allows the stratification of risk. Compli-cations are by far more common in monochorionic twin pregnancies. They include preterm delivery (in Portugal, out of 7551 newborns of very low birth weight born between 1996 and 2003, 25.6% resulted from multiple gestations), fetal malformations, twin-to-twin transfusion syndrome, twin embolization syndrome, intrauterine death of one fetus, and neurologic handicap secondary to hypotensive episodes caused by drain-back flow from the live fetus into the dead fetoplacental unit through vascular anastomoses.^{19,20, and 21}

In the days before ultrasound, when the obstetrician delivered a set of twins, traditionally the first one to be delivered was called "twin A" and the second "twin B" (Figure 13-13). By some twisted extrapolation, this nomenclature has been applied to ultrasound, although we have observed that the presenting twin is not always the same one from examination to examination. A much better terminology is to describe the relative positions of the twins (left upper and right lower, for instance) because, aside from rare exceptions, the membrane prevents the twins from switching sides. Rarely active twins may have a redundant intertwin membrane that allows one twin to "cross over" its sibling. By tracing the position of the membrane the condition can be identified and recognized from amniotic bands or the "folding membrane" sign.

Definition

Monoamniotic twins share not only the chorion (the outer membrane) but also the amnion (the inner membrane) and thus are in the same gestational sac (Figure 13-14). They result from splitting between 7 and 13 days after fertilization and represent 1% of twin pregnancies resulting in a shared chorion and a single amniotic cavity. Interestingly, monoamniotic-monochorionic placentas have significantly greater numbers of both superficial and deep anastomoses than do uncomplicated monochorionic diamniotic pregnancies. This observation suggests a vascular basis for the extreme rarity of twin-to-twin transfusion syndrome in monoamniotic pregnancies.²²

Sonographic Features

Differentiating monochorionic diamniotic from monochorionic monoamniotic twins is not easy, but it is very important because it identifies patients at higher risk for cord accidents.

Monoamniotic twins can be suspected if the following features are observed (Figures 13-15,13-16, and 13-17).

• Single-placenta and same-sex twins

• Absence of a dividing membrane, namely in the 3 planes of three-dimensional ultrasound

• Insertion of both cords very close to each other

• Entanglement of the cords,²³ demonstrated by color or power Doppler

• Normal amniotic fluid volume around both fetuses

• Visualization of a single yolk sac early in pregnancy (not always reliable)

• Observation of the passive motion of the embryos when the patient is rolled to the side

Differential Diagnosis

Monoamniotic twins can easily be confused with monochorionic diamniotic twins, especially when there is twin-to-twin transfusion and one of the twins is stuck (see elsewhere in this chapter). A careful search for a membrane is the only way to ascertain the diagnosis. The absence or reduced amniotic fluid around the stuck twin also should raise the suspicion of a diamniotic gestation.

Associated Syndromes

Monoamniotic twins may be affected by multiple pathologic conditions including twin-to-twin transfusion (although much less commonly than in monochorionic diamniotic twins), entangled umbilical cords,^23,24 and increased risk of congenital anomalies (15% to 20%).

Cord entanglement occurs in 40% to 70% of monoamniotic twins because of their increased mobility in the second trimester, and can be seen as early as the first trimester. During the third trimester, the reduced space is usually no longer sufficient to allow the twins to move around. In cases of cord entanglement, despite apparent cord compression with absent end-diastolic velocities (AEDVs), some fetuses may grow appropriately. The significance of AEDV in monoamniotic twins may thus be less predictive than in singletons. The presence of a notch in the umbilical artery velocity waveform may reflect narrowing of the umbilical vessels involved in cord entanglement. Because of these complications, the overall perinatal mortality for monoamniotic twins can be as high as 50% to 60%.²³

Definition

Conjoined twins are monochorionic monoamniotic twins fused at any portion of their bodies as a result of an incomplete division of the embryonic disk, after the 13th day of conception (Figure 13-18).²⁵ The term conjoined is actually a misnomer because most researchers consider the pathogenesis of the condition to result from failure of complete separation rather than from fusion of the twins.

This is a rare condition and the reported frequency differs from 0.1 to 0.35 per 10,000 births.²⁶ If stillborns are excluded, the estimate is 0.05 per 10,000 births. Females are more commonly affected, with a male-to-female ratio of 1.6–3 to 1. No association with maternal age, race, parity, or heredity has been observed. The recurrence risk is negligible.

Sonographic Features

Several sonographic signs can be observed in this condition, as follows:

• Absence of an interamniotic membrane between the twins

• Inability to separate fetal bodies

• Fixed position of the fetuses relative one to another, even after external stimulation or maternal movement

• Bifid appearance of the first-trimester fetal pole (V- or Y-shaped twin pregnancy) and continuous skin contours at the same anatomic level

• The heads and bodies of both twins are seen at the same level (Figures 13-19 and 13-20)

• Unusual extension of the spines

• Unusual proximity of the extremities

• Presence of a single heart (Figure 13-21)

• Abnormal number of vessels (more than 3) in the umbilical cord

The presence of these signs changes according to the different types of conjoined twins. These must be considered whenever a monochorionic and monoamniotic pregnancy is suspected. Discordant presentation does not exclude conjoined twins. Although the diagnosis of conjoined twins is easier during the first trimester, the type and severity of the condition is better achieved during the second trimester, when a more precise evaluation of the shared organs can be done. Diagnosis with three-dimensional transvaginal sonography during the first trimester has also been described. If diagnosis is made before viability, termination of pregnancy can be offered.

Classification

Conjoined twins are classified according to the area of the bodies where the fusion takes place. The symmetrical and equal forms, in which the twins have equal or nearly equal duplication of structures, are called duplicata completa. Whenever there is an unequal duplication of structures, the twins are called duplicata incompleta, and this category includes the most severe types of conjoined twins in which just a few organs systems are duplicated. The most frequent varieties of conjoined twins are thoracopagus (40% to 74%), omphalopagus (10% to 33%), pygopagus (18%), ischiopagus (6%), and craniopagus (1% to 6%). The classification of conjoined twins is described in Table 13-2.

• Duplicata Incompleta. Duplication occurring in only one part or region of the body (Figure 13-22). Examples are diprosopus (1 body, 1 head, and 2 faces), dicephalus (1 body and 2 heads), and dipygus (1 head, thorax and abdomen with 2 pelvises, and/or external genitalia).

• Duplicata Completa. Two complete conjoined twins.

• Terata Catadidyma. Conjunction in the lower part of the body (Figure 13-23). Examples are ischiopagus (joined by the inferior portion of the coccyx and sacrum) and pygopagus (joined by the lateral and posterior portions of the coccyx and sacrum).

• Terata Anadidyma. Conjunction in the upper part of the body (Figure 13-24). Examples are syncephalus (joined by the face) and craniopagus (joined at the homologous portion of the cranial vault).

• Terata Anacatadidyma. Conjunction at the midpart of the body (Figure 13-25). Examples are thoracopagus (joined at the thoracic wall), xiphopagus (joined at the xiphoid process), omphalopagus (joined at the area between the xiphoid cartilage and the umbilicus), and rachipagus (joined at the level of the spine above the sacrum).

  Meanwhile, a new classification has been proposed based on the theoretical site of union.

• Ventral Union. Twins united along the ventral aspect.

• Cephalopagus. The twins are fused from the top of the head down to the umbilicus. There are 2 rudimentary (fused) faces, 4 arms, and 4 legs. The lower abdomen and pelvis are separated. The cephalothoracopagus janiceps type is a rare variety of conjoined twins in which the fetuses are joined face to face, with the face of each fetus being split at the midline and in half turned outward, so that each observed face is made up of the right face of one fetus and the left face of the other. The name originates from Janus in Roman mythology, the god of gates and doorways; his statue has 2 faces, facing east and west, representing the beginning and ending of the day, and 1 head.

• Thoracopagus. The twins are united face to face from the upper thorax down to the umbilicus; the heart is always involved. There are 4 arms, 4 legs, and 2 pelvises.

• Omphalopagus. The twins are joined face to face primarily in the area of the umbilicus and sometimes involving the lower thorax, but 2 distinct hearts are always preserved. There are 2 pelvises, 4 arms, and 4 legs.

• Ischiopagus. The twins are united ventrally from the umbilicus to a large conjoined pelvis with 2 sacrums and 2 symphyses pubises. They appear more frequently joined end to end, with the spine in a straight line, but they can also present face to face with a joined abdomen. There are 4 arms, 4 legs, and, in general, a common external genitalia and a common anus.

• Lateral Union. Twins are joined side by side, with shared umbilicus, abdomen, and pelvis.

• Parapagus. These twins share a conjoined pelvis, 1 symphysis pubis, and 1 or 2 sacrums. When the union is limited to the abdomen and pelvis (does not involve the thorax), it is called dithoracic parapagus. If there is 1 trunk with 2 heads, it is called dicephalic parapagus. If there is a single trunk and a single head with 2 faces, it is called diprosopic parapagus. There are 2, 3, or 4 arms and 2 or 3 legs.

• Dorsal Union. Twins are joined at the dorsal aspect of the primitive embryonic disk. There is no involvement of the thorax and abdomen.

• Craniopagus. Twins are united at any portion of the skull, except the face or foramen magnum. They share bones of the cranium, meninges, and occasionally brain surface. There are 2 trunks, 4 arms, and 4 legs.

• Pygopagus. Twins share dorsally the sacrococcygeal, perineal regions, and occasionally the spinal cord. There are 1 anus, 2 rectums, 4 arms, and 4 legs.

• Rachipagus. Twins are fused dorsally above the sacrum, involving different segments of the column. This type is extremely rare.

Differential Diagnosis

Conjoined twins have a unique presentation and the few differential diagnoses could include lymphangioma, teratoma, or cystic hygroma.

Associated Syndromes

Congenital anomalies of organs other than the shared ones are present in 50% of cases of conjoined twins. Cardiac defects are the most common association (20% to 30%); thus, echocardiography is recommended in all cases. Neural tube defects and midline fusion defects, orofacial clefts, imperforate anus, and diaphragmatic hernia are also frequently seen. Polyhydramnios is observed in 50% to 75% of cases.

Prognosis

Most conjoined twins are born prematurely, 40% are stillborn, and 35% die within 24 hours.²⁶ Among the survivors, the prognosis and attempts in surgical separation will depend on the type of conjunction, degree of involvement of the shared organs, and the presence of associated anomalies. The most ominous prognosis was found among those twins who shared liver and/or heart. Attempts of separation in cases of a common liver can be done as long as 2 biliary tracts are seen. In the presence of a shared heart, separation is only attempted if 2 normal hearts coexist in a single pericardium.

Management

The method of choice for delivery is cesarean section to maximize survival and prevent maternal and fetal trauma.

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.

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.

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:

1. Vascular anastomoses: Combination of type of connections (number, type, and diameter) and direction of connections.

2. 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

3. 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.

4. 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.

5. 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:

• A difference in cord hemoglobin concentrations of 5 g/dL or more

• A difference in birth weights of 20% or more

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):

1. 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.

2. 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.

3. 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}

4. Fetal echocardiography

   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.

5. 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.

6. 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 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).

Timing

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.

Prognosis

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.

Management

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

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

Differential Diagnosis

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.

Associated Complications

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.

Nuchal Translucency

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

Ductus Venosus Flowmetry

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.

Arterio-Arterial Anastomoses

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

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).

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.

Differential Diagnosis

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

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.

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

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%.

Management

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.

Differential Diagnosis

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.

Associated Syndromes

There are no associated syndromes.

Fetus In Fetu

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.

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).

Synonyms

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.

Etiology

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

Pathogenesis

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).

Localization

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.

Vascularization

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.

Age at Detection

Only a few cases have been detected prenatally. Most cases are discovered in newborns or small children.

Weight

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.

Number

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.

Zygosity

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.

Macroscopic Appearance

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.

What Is Included

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.

Differential Diagnosis

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.

Associated Anomalies

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.

Evolution

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.

Prognosis

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.

Recurrence Risk

There is no report of recurrence.

Management

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.

Ultrasound is particularly useful for recording fetal demise. The 3 common forms of spontaneous fetal loss in multiple gestation are (1) the vanishing twin syndrome, which occurs in the first trimester; (2) the fetus papyraceous in the second trimester; and (3) stillbirth in the third trimester.

Vanishing twin is the first-trimester loss of a member of a twin gestation.⁷⁰ The incidence of twinning has been reported to be 3.29%, and of these 21.2% have demonstrated the vanishing twin phenomenon.^20,71 The vanishing twin is simply reabsorbed.

This phenomenon is believed to have postnatal consequences. A significant proportion of cases with spastic cerebral palsy in apparent singletons may be attributable to ischemic cerebral impairment in a monochorionic twin pregnancy in which the co-twin suffered very early loss.²⁰ In fact, where co-twins are known to have died in the womb, the prevalence of cerebral palsy in the surviving twin is 82 of 1000 (versus singletons, affected in 2 of 1000) live births.

Sonographic Features

The gestational sac is small, and the development of one fetus lags behind that of the other fetus; there is no detectable fetal heart activity. The spectrum varies, from a crescent-shaped sac adjacent to a normal early gestation (between 10 and 14 weeks), to a well-formed but dead fetus (fetus papyraceous in the second trimester). Early vanishing twins should be distinguished from implantation bleeds that are not surrounded by a trophoblastic ring. Sonographic evaluation of early gestational bleeds frequently leads to the diagnosis of a vanishing twin, and this is apparently the single complication associated with the disappearance of a twin at this stage.²⁰ A vanishing twin does not adversely affect the development of a coexisting singleton pregnancy; therefore, the exact distinction between implantation bleed and vanishing twin may be academic (Figures 13-49,13-50,13-51, and 13-52).

Differential Diagnosis

The differential diagnosis includes implantation bleeds in the early pregnancy, artifactual error (rectus muscle artifact), incomplete scanning technique, poor-quality ultrasound equipment, and placental cysts after the second trimester.

Associated Syndromes

Fetus papyraceus is a macerated fetus delivered with a normal co-twin and is usually embedded in the placental membranes.

Papyraceous fetus is characterized by a macerated fetus (Figure 13-53) resulting from an early loss (second trimester) of one twin, and it may affect both mono- and dichorionic gestations. The nonviable fetus is compressed by the expanding sac of the co-twin and partially absorbed throughout the pregnancy. The surviving twin often has sequelae of twin embolization syndrome such as aplasia cutis, a rare disorder characterized by localized absence of skin.

Chromosomal abnormalities are more frequent in multiple pregnancies than in the general population. In DZ pregnancies, 2 oocytes are fertilized and each oocyte has an inherent risk of a chromosomal anomaly. The result is an increased rate of chromosomal abnormalities for any given maternal age. The relative proportion of spontaneous dizygotic to monozygotic is about 2:1, and therefore the prevalence of chromosomal abnormalities affecting at least 1 fetus in a twin pregnancy would be expected to be about 1.6 times that in singletons.

Rodis et al⁹ constructed a nomogram for the calculation of risk of chromosomal abnormalities in twin gestations. For example, a 33-year-old mother with a twin gestation carries the same risk of chromosomal abnormalities as a 35-year-old woman with a singleton pregnancy. This concept has clinical implications in the management of twin gestations and the maternal age at which cytogenetic studies should be offered.

Fetal sex assignment can be another useful bit of information, particularly in pregnancies at risk for severe sex-linked diseases and fetal disorders involving the genitalia.⁷² It is worth mentioning that there have been reports of discordant sex in monozygous twins.⁷³

Monozygotic twins are highly concordant for minor anomalies, tend to be concordant for rare congenital defects and malformations, and are predominantly discordant for more common major malformations. In general, the smaller twin is the more severely affected. There are reports of discordant karyotype in identical twins, with the recommendation of sampling both sacs if 1 or both fetuses present ultrasound abnormalities, even if the scan suggests a monochorionic pregnancy. This technique must be performed carefully by making sure that each sample is properly attributed to the correspondent twin. There is a small possibility of heterokaryotypic MZ twins resulting from a mitotic nondisjunction after the zygote splits (Figures 13-54 and 13-55). There are occasional reports of MZ twins discordant for abnormalities of autosomes or sex chromosomes, such as Klinefelter syndrome with inversion of chromosome 13 in the co-twin, trisomy 13, Turner syndrome and other aneuploidies, and gonadal dysgenesis.

In fact, twins present unique and problematic issues in prenatal diagnosis. The performance of screening tests designed for singleton pregnancies is altered. Having correctly established the chorionicity, specific aspects of prenatal screening and diagnosis can be adequately planned in multiple pregnancies since chromosomal abnormalities in twin pregnancies raise serious clinical, ethical, and moral problems that need to be addressed:

• Effective methods of screening, such as maternal serum biochemistry, have lower detection rates.

• In the presence of a "screen-positive" biochemical result, there is no feature to suggest which fetus may be affected.

• The techniques of invasive testing are technically more difficult in twins, and sometimes it may be almost impossible to ensure that fetal tissue is obtained from each fetus.

• There is an increased risk of miscarriage for any invasive test in twins.

• Selection of the adequate invasive test to offer.

• The difficulties of clinical management in cases of selective fetal reduction and the potential increased risk to the unaffected co-twin.

The overall probability that a multiple gestation contains an aneuploid fetus is directly related to its zygosity. In DZ pregnancies, each fetus has an independent risk of aneuploidy; thus, the maternal age-related risk for chromosomal abnormalities for each twin may be the same as in singleton pregnancies, but the chance that at least 1 fetus will be affected by a chromosomal defect is twice as high as in singleton pregnancies.⁷⁶ This means that for DZ twin pregnancies, the pregnancy-specific risk is calculated by summing the individual risk estimates for each fetus. The 10% of DC twin pregnancies that are monozygotic will incorrectly have their risks calculated by the summing rather than the averaging method. However, the ultimate effect on screening performance will be a negligible one.

In monozygotic twins, the risk of an affected fetus approximates the maternal age risk of a singleton pregnancy and, in the vast majority of cases, the risk for one fetus is, as expected, the same as the risk for the other.⁷⁶ Presumably, both will be affected or both will be unaffected. The most reliable and reproducible method of screening in twins is NT. It is therefore appropriate to take the average of the 2 NT measurements, so that a single risk estimate can be calculated (averaging method).

If zygosity is unknown, the risk of at least 1 aneuploid fetus can be approximated as five-thirds that of the singleton risk. This is based on the assumption that a third of all twin pairs are monozygotic. Counselling based on chorionicity, though an oversimplification (only about 90% of DC pregnancies are dizygotic), is clinically more feasible than zygosity (Figures 13-56 and 13-57).

If the pregnancy is dichorionic, then the parents should be counselled that the risk of discordance for a chromosomal abnormality is about twice that in singleton pregnancies, whereas the risk that both fetuses would be affected corresponds to the singleton risk squared. However, with higher risk conditions, such as autosomal recessive disorders, this could be as high as 1 in 16. For example, in a 40-year-old pregnant woman with a risk for trisomy of about 1 in 100 based on maternal age, in a DZ twin pregnancy the risk that one fetus would be affected would be 1 in 50 (1 in 100 plus 1 in 100), whereas the risk that both fetuses would be affected is 1 in 10,000 (1 in 100 × 1 in 100).

When calculating the risk of higher order multiples, estimates can be made multiplying the singleton risk by the number of fetuses. This method assumes unique chorionicity for each fetus, though monozygosity can occur more frequently than usually thought at higher rates in ART multiple gestations.^4,5

The possibility of deriving a risk for trisomy 21 from NT assessment in the first trimester of pregnancy shifted the consideration of a pregnancy-specific risk to a fetus-specific risk.^75,76 This assumption was based on the observation that the distribution of NT measurements in twin fetuses with trisomy 21 was similar to that in singletons.⁷³ The higher rate of false positives for NT among monochorionic twins (8.4%) should be ascribed to the possibility of early hemodynamic imbalance (the risk of developing twin-to-twin transfusion syndrome if NT is increased is augmented 3- to 5-fold).^48,49 In contrast, though biochemical screening in twins was the first alternative to age-derived risk, it clearly has a lower detection rate for fetal aneuploidies (50%) and higher rates of false positives.⁷⁷ This kind of screening only permits the calculation of a pregnancy-specific and not a fetus-specific risk. In twin pregnancies, the levels of maternal serum markers are, on average, expected to be about twice as high in unaffected twin pregnancies as in unaffected singleton pregnancies, that is, proportional to the number of fetoplacental units. However, as biochemical screening in twins is still investigational and far less powerful than in singletons, it should not be recommended in general practice without extensive counselling.

Diagnostic Amniocentesis

When karyotyping is recommended, chorionic villus sampling is an early and safe technique of prenatal diagnosis in multiple pregnancies.⁷⁸ If the invasive procedure is performed after 16 weeks, amniocentesis should be the first choice. However, it should be considered that the risk of pregnancy loss when amniocentesis is performed in twins is higher than in singletons.⁷⁹ Some investigators have attributed this increased loss rate to the natural tendency of miscarriage observed in multiple gestations.

In order to differentiate one sac from the other (Figure 13-58), different techniques have been employed, such as the injection of dye or air into one of the amniotic cavities. Since 1990, the avoidance of methylene dye in prenatal diagnosis has been recommended because of its fetotoxity and a weak association with intestinal atresia. A single puncture can be used with no need of dye or air injection, with the advantages of being less invasive and less painful (Figure 13-59).⁸⁰

Amniocentesis may also have therapeutic applications, in particular, in acute polyhydramnios, caused by twin-to-twin transfusion syndrome or fetal malformations, with elevated perinatal mortality if not treated. The overdistention of the uterus provokes maternal discomfort, premature labor, and premature rupture of membranes. The treatment consists of serial amniocenteses to normalize the intrauterine pressure, prevent premature labor, and relieve maternal symptoms (see Twin-to-Twin Transfusion Syndrome, above).

The restriction of intrauterine fetal growth is more frequently found in multiple pregnancies: about 52% of twins and 92% of triplets present with low birth weight (<2500 g) compared to 6% of singletons, whereas 10% of twins and 32% of triplets are born with very low birth weight (<1000 g) when compared to 1% of singletons. When talking about fetal growth in multiple pregnancies one should consider several limitations: first, it is believed that multiples do not have the same growth potential as singletons, and there are serious doubts concerning the appropriateness of singleton standards for multiples.

If we monitor fetal growth in multiple pregnancies by singleton standards, more than 50% of triplets are considered small for gestational age (SGA) at 35 weeks, and more than 50% of twins are considered SGA at 38 weeks. The average birth weight at 39 weeks is 3357 g, at 35.8 weeks is 2389 g, and at 32.5 weeks is 1735 g, for singletons, twins, and triplets, respectively.

Second, the growth pattern of late pregnancy is practically unknown because preterm birth (by singleton standards) is the rule rather than the exception in multiple gestations (before 37 weeks, about 50% of twins and 91% of triplets were already born in comparison with 9% of singletons). Finally, there are few longitudinal studies, and most of our knowledge is derived from birth weight by gestational age relationships (growth curves). Serial growth assessment is the most accurate method to diagnose intrauterine growth restriction (IUGR).

Though many authors classify twin infants as IUGR by using a gender- and a gestational age–specific birth weight at or below the 10th centile.^81,82 the truth is that a biological phenomenon with a frequency of over 50% reluctantly will be considered a pathological event. The re-evaluation of the median birth weight centile of twins and triplets compared to the 10th centile for singletons showed that the average multiple is not "SGA" and weighs more than the 10th birth weight percentile for singletons until 35 weeks in triplets and 38 weeks in twins (Figure 13-60).⁸²

Most of the multiples are not growth restricted; they only grow differently. The common growth curves show that deviations from singleton standards occur after 28 weeks.⁸³ Growth rate in multiple gestations during the first and early second trimesters parallels the growth rate of singleton pregnancies, dropping off during the late second and third trimesters (Figure 13-61).

The uterine milieu, comprising uteroplacental, maternal, and fetal components, limits physiologically the growth potential of the individual fetus in a multiple pregnancy (Figure 13-62). This concept implies that most multiples delivered after 28 weeks are growth restricted compared to singletons, as a result of an adaptative process. Data from 147,575 twins pairs and 5172 triplets sets (1995 to 1997 Matched Multiple Birth Data Set do National Center for Health statistics)⁸¹ showed that the total twin and total triplet birth weights exceed that of the 90th birth weight centile for singletons as early as 25 weeks' gestation (data derived from 3.6 million singletons).

The risk of fetal growth restriction in a multiple pregnancy is 10 times greater than in a singleton pregnancy,^81,84,85 being even greater in a monochorionic (34%) compared to a DC pregnancy (23%).⁷ Hence, the meaning of fetal growth discordance in multiples depends on chorionicity. The abdominal circumference is the most reliable sonographic criterion for the establishment of growth discrepancy. A difference of 20 mm translates in a birth weight discrepancy of 20% or more. In a DC twin pregnancy (dizygotic in 90%) discrepant growth may be ascribed to a different genetic constitution of the twins or to an unequal placental function. In a monochorionic pregnancy, as the genetic content is the same, the growth discordance may be due to an unequal division of the cellular mass (unequal sharing of the placenta), velamentous insertion of the cord, or the unbalanced transfusion of blood through the vascular anastomoses. Twin-to-twin transfusion syndrome is the main differential diagnosis. Interestingly, twin pregnancies resulting from in vitro fertilization or gamete intrafallopian transfer are more likely to result in birth weight discordance and in fetuses with high serum α-fetoprotein levels.

Sonographic findings suggestive of growth discrepancy include the following:

• Estimated fetal weights that are discordant by more than 20%; discordance can be classified as mild (15% to 25%) or severe (>25%).

• Abdominal circumference diverging by 20 mm or more.

• Umbilical artery systolic-to-diastolic ratios that are discordant by more than 15% and an elevated umbilical artery systolic-to-diastolic ratio (≥0.4) in one or both twins.⁸⁶

A very important point is that neonatal mortality and morbidity was significantly higher (29.1%) when the smaller twin weighed less than the 10th centile for gestational age compared with those pairs in which the smaller twin was above the 10th centile.^{87,88,89, and 90} The data prove that even among severely discordant pairs, 40% are appropriately grown twins, of which 6% are, in fact, growth promoted.⁸³

A final note about growth discrepancy in the first trimester of pregnancy: a study on normal twin pregnancies, excluding cases that subsequently developed twin-to-twin transfusion syndrome, discordance in crown-rump length lower than the 95th centile was not associated with adverse perinatal outcome, but twins with a larger discordance had a poor outcome.⁹¹

Membranous insertion of the placenta is a complication that mainly affects higher-order gestations (triplets or higher). The incidence of velamentous insertion in monochorionic twin placentas (mainly in the donor) is 12% (32% in twin-to-twin transfusion syndrome) (versus 2% in singletons and 7% in DC pregnancies) with consequent unequal placental territories and uteroplacental insufficiency (Figure 13-63).⁹²

In such pregnancies, a centrally located fetus may have a trophoblast developing predominantly on the uterine tissue between the gestational sacs of the other embryos. As the sac grows, that trophoblast will transform into a placenta that is predominantly over the membranes of the other embryos. Even with trophotropism (the tendency of the placenta to preferentially develop where maternal exchanges are best), this embryo is at great risk of growth restriction. Should a fetal reduction be considered, this embryo would be a prime candidate.

Multiple gestations have approximately twice as many congenital anomalies when compared with the expected rate for the general population.⁹ Major anomalies are seen in 2.1% of twins versus 1.2% of singletons, whereas minor anomalies are seen in 4.1% of twins versus 2.4% of singletons. Monozygotic twins show an excess (2 to 3 times higher) of structural defects as compared to DZ twins and singletons.⁹ The reported incidence of anomalies in MZ twins is approximately 16.7% for minor anomalies and an additional 16.7% for major anomalies. If a malformation is observed in one twin, the other has a high chance of being equally affected. Concordance, however, is seen in 10% of DC twins and in 10% to 20% of MZ twins.

A careful anatomy survey is necessary to exclude a discordant anomaly, especially in MZ pairs. The discordance in DZ twins is due to a genetic predisposition. In the MZ pregnancy this discordance is more prevalent and may be explained by the following:

• Variable gene expression (post-zygotic mutation, asymmetrical X inactivation).

• Occurrence of an early defect in the process of splitting or a delay or asymmetry at the splitting of the embryo that should cause structural anomalies in the fetuses. The ultimate example of this theory is conjoined twins.

• Splitting after laterality gradients have been established (midline defects and cardiac).

• Fetal anomalies may be attributed to a vascular compromise secondary to a shared placenta, putatively responsible for disruptions (porencephaly, multicystic encephalomalacia, hemifacial microsomia, amyoplasia, bowel atresia). Syndromes that relate to this etiology include twin reversed arterial perfusion, twin-to-twin transfusion syndrome, and twin embolization syndrome.

• Crowding of the uterine cavity may be associated with certain types of anomalies. This would explain the statistically significant concordance seen in musculoskeletal abnormalities in MZ twinning, such as clubfeet and arthrogryposis.⁹³

Some of the anomalies reported in multiple gestations are cloacal dysgenesis sequence, cyclopia, amniotic band disruption complex, ventral body wall anomalies, cystic hygroma, cerebral and ocular abnormalities, microcephaly, and VATER (vertebral defects, anal atresia, tracheoesophageal fistula with esophageal atresia, and radial and renal anomalies) association, among others.

Monozygotic twins are usually discordant for malformations such as cardiac and urinary tract defects, omphalocele, and neural tube defects (Figure 13-64), but are usually concordant for malformations such as cloacal dysgenesis and omphalocele-exstrophy-imperforate anus-spinal defects syndrome.

Pseudo-concordance of malformations may occur in MZ twins. Though they are frequently discordant for thyroid dysgenesis, both may only be mildly ill. Due to interfetal connections, the affected fetus may be protected from hypothyroidism by the transplacental transfusion of thyroxin from the thyroid of the unaffected co-twin and present at birth with almost normal thyroxin levels.

Another example of pseudo-concordance of phenotype exists for monoamniotic twins with urinary tract malformations, in which the anuric fetus is protected from pulmonary hypoplasia and deformities by the urine output from the other fetus.

Multifetal pregnancy reduction is the elective termination of a variable number of fetuses, preferably done between the 10th and the 13th weeks of gestation, to improve the perinatal outcome of the remaining fetuses.^94,95 It is well known that higher-order multiple gestations have increased risks for both maternal and fetal complications, and the most common are loss of the entire pregnancy, maternal high blood pressure, IUGR, premature rupture of membranes, and preterm delivery. The occurrence of any of these events increases the risk of perinatal death and that of sequelae, such as interventricular hemorrhage, cerebral palsy, retinopathy, and respiratory diseases. The procedure may improve maternal and fetal conditions, thereby reducing the risk of prematurity and its associated complications. Although it confers unequivocal benefits to the pregnancy when successful, fetal reduction itself carries risks. The risk of losing the entire pregnancy is the major concern and occurs in approximately 12% of cases.

Basically, the procedure consists of a transabdominal needle injection of potassium chloride into the fetal thorax. If reduction of both fetuses of a monochorionic pair is desired, the procedure may be successfully accomplished with a single injection in one of the pair. Special attention should be given to the appropriate use of the terminology selective termination and elective fetal reduction. Although both are procedures applied only in multiple gestations, there are some differences between them.

Selective termination is a procedure in which an anomalous fetus in a multifetal pregnancy is terminated to improve the prognosis of the normal co-twin.^94,95 It is usually a second trimester procedure that follows the same routine as a first trimester reduction.

Elective fetal reduction describes the reduction of triplets or higher-order fetuses to a smaller set (in general, to twins) for medical, psychological, and socioeconomic reasons, thus improving the outcome of the remaining fetuses and reducing the maternal risks. Some controversy still persists regarding the impact of fetal reduction from triplets to twins. Some investigators have stated that triplet-to-twin fetal reduction significantly reduces the risk for prematurity and low birth weight and may even be associated with a reduction of the overall pregnancy loss rate, suggesting that it is a medically justifiable procedure and should be offered in these cases.^94,96 Others who recommend the maintenance of the entire pregnancy have stated that bed rest starting at the 20th week of gestation and close prenatal care reduce the prematurity rate and optimize fetal growth, thereby improving the outcome to the levels of a twin pregnancy.

Selective termination can be performed any time during pregnancy, with good outcome in approximately 90% of cases and a total pregnancy loss rate of 11.7%.^94,95

Preterm delivery is one of the most important issues affecting infant health of future generations. Prematurity is responsible for half of the cases of long-term neurologic impairment and three-quarters of neonatal mortality in children. Half of the multiples are low birth weight, and 30% are very low birth weight.

Multiple birth rates are steadily increasing worldwide and range from 11.7% in Italy to 18.9% in the Netherlands.⁹⁶ Multiples account for 18% to 25% of preterm births, and half of the children from multiple pregnancies are born preterm in the European Community countries.⁹⁶

One in eight babies (12% of liveborn infants) is born preterm in the United States. Assisted reproductive techniques (ART) increase by 2-fold the risk of preterm delivery in twins versus spontaneously conceived children.⁹⁷ We should bear in mind that ART accounts for 1% of all births, 12% of twins, and 45% of higher-order multiples.

Preterm delivery is increased due to the higher frequency of premature rupture of the membranes (7% versus 4%) and marked uterine distention. Furthermore, multiples are more often iatrogenically terminated, and there is a greater tendency for clinicians to intervene.

Cervical length assessment at 22 to 24 weeks of gestation⁹⁸ demonstrated that in both singletons and twins, a cervical length of 40 mm or more was associated with a less than 1% rate of preterm delivery.⁹⁹ However, for a cervical length of less than 10 mm (Figure 13-65), 80% of singletons and 66% of twins would deliver preterm.

Further investigation by To et al¹⁰⁰ pointed to a threshold exponential increase in preterm delivery for singletons at 15 mm, and for multiples at 25 mm. In other words, the risk of preterm delivery in multiples for a cervical length 25 mm or less is similar to that of singletons with a cervical length of 15 mm or less.¹⁰⁰

Cervical cerclage in multiple gestations remains a controversial issue in prenatal care.^101,102 Some investigators have demonstrated a satisfactory fetal survival rate with minimal incidence of maternal complications postcerclage, and thus recommend the routine use of the procedure in multiple pregnancies.^101,102 Other groups have shown a higher risk for premature rupture of membranes with no evident benefit for the pregnancy outcome. We believe the twin pregnancy by itself does not justify the procedure. In multiple pregnancies with sets of triplets or more, the cerclage should be discussed with the patient, considering risks and benefits in each case. If there is a history of cervical incompetence, the procedure must be offered independently of the number of fetuses.

Acknowledgments

The authors are greatly indebted to Jacqueline Reyes, Luís Flávio de Andrade Gonçalves, and Sandra Rejane Silva for the previous version of this chapter, which served as the basis for this update. This chapter was originally published on www.TheFetus.net (© 2000 Philippe Jeanty).

Some images are courtesy of Gianluigi Pilu and Isaac Blickstein. A few drawings were adapted from Lifeart by the Techpool studio.

A final word for Isaac Blickstein: a very special friend to whom I owe my passion for twins and with whom I have learned so much about multiple pregnancies.