twin-to-twin transfusion syndrome : part 1. types and ... · matically derived vascular models and...

DOI: 10.1542/neo.9-9-e3702008;9;e370Neoreviews

Ona M. Faye-Petersen and Timothy M. CrombleholmeTwin-to-Twin Transfusion Syndrome : Part 1. Types and Pathogenesis

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Twin-to-Twin TransfusionSyndrome:Part 1. Types and PathogenesisOna M. Faye-Petersen,

MD,* Timothy M.

Crombleholme, MD†

Author Disclosure

Drs Faye-Petersen and

Crombleholme have

disclosed no financial

relationships relevant

to this article. This

commentary does not

contain a discussion

of an unapproved/

investigative use of a

commercial product/

device.

Objectives After completing this article, readers should be able to:

1. Differentiate acute and chronic twin-to-twin transfusion syndrome (TTTS).2. Describe the role of placental anastomoses in TTTS.3. List the primary factors contributing to the development of TTTS.4. Describe characteristics of the placenta in the presence of TTTS.5. Characterize fetal adaptations to TTTS.

AbstractTwin-to-twin transfusion syndrome (TTTS) may be acute or chronic, but chronicTTTS complicates 10% to 20% of monochorionic twin gestations and has an 80% to100% mortality rate if severe and left untreated. Both types are due to the presence ofplacental anastomoses between the two twins, but the mechanisms involved in thedevelopment of chronic TTTS are particularly complex and incompletely understood.Many of the apparent pathogenic mechanisms have implications for the appearancesand cardiovascular and physiologic disturbances of neonates born following thisintrauterine condition and their response to treatment. We present an update in thepathogenesis of TTTS that includes an overview of the placental features, fetaladaptive and maladaptive responses, and molecular mechanisms involved in thedevelopment of TTTS.

IntroductionTwin-to-twin transfusion syndrome (TTTS) is a gestational condition in which thecirculation of one twin and the other communicate via placental anastomoses. It is almostexclusively restricted to monochorionic (monozygotic) twins with diamniotic monocho-rionic (DiMo) placentations and clinically presents as two types, acute and chronic. Rarely,TTTS can occur in dichorionic gestations but only if there is a vascular connection betweenthe two circulations.

Acute, clinically relevant TTTS is rare and usually occurs during delivery from a suddenhemodynamic incident, such as cord compression or vascular rupture with vasa praevia thataffects only one of the twins. (1)(2) In these instances, the twins are of similar birthweight,but due to peripartum acute shift(s) of blood through large, chorionic plate anastomoses,(3) most commonly large venovenous anastomoses, (4) one twin is pale and the other isplethoric. Initially, both twins may have similar hematocrit and hemoglobin values or theplethoric twin has an increased erythrocyte count and hemoglobin. However, the pale twinbecomes notably anemic within hours of birth, as intravascular volume is reconstituted.(3)(5) Acute transfusion syndrome also may occur with delivery of the first twin, with thefirst twin draining blood into the second prior to clamping of the first twin’s cord.Alternatively, following delivery and clamping of the cord of the first twin, blood may flowrapidly from the second twin across placental anastomoses into the monochorionicplacenta due to the sudden drop in blood pressure within the placental angioarchitectureperfused by the first twin. A similar scenario of acute transfusion can occur with intrauter-

*Associate Professor of Pathology and Obstetrics and Gynecology; Head, Microdissection Laboratory, Division of AnatomicPathology, The University of Alabama at Birmingham, Birmingham, Ala.†Director, Fetal Care Center of Cincinnati; Professor of Surgery, Pediatrics, and Obstetrics and Gynecology, University ofCincinnati College of Medicine; Division of Pediatric General, Thoracic, and Fetal Surgery, Cincinnati Children’s HospitalMedical Center, Cincinnati, Ohio.

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ine fetal death of one twin; the placenta of the dead twinbecomes a low-resistance vascular tree, and the viabletwin may partially or quickly exsanguinate into the pla-centa. The sudden hypotension may result in the demiseof the second twin or significant ischemic brain injury ifthe co-twin survives the hypotensive episode. Finally, anacute event can complicate chronic TTTS suddenly andreverse the prior donor-recipient relationship. Thus, al-though rare, acute TTTS may explain otherwise confus-ing or paradoxic findings on antenatal ultrasonographyor at delivery. (1)(5) Careful examination of the placentain these clinical settings, with assessment of the presenceand types of vascular communications, can play a role indetermining the cause of unexpected neonatal hemoglo-bin values or newborn morbidities or sudden mortality.

Chronic TTTS, hereafter designated simply as TTTS,is a condition of a sustained, net imbalance of bloodvolume transfused between twins of a DiMo placenta-tion. Purportedly due to inter-twin vascular anastomosesin the placenta, one twin becomes the net donor and theco-twin becomes the effective recipient. TTTS generallyis stated to complicate 10% to 20% of all monochorionictwin gestations, but inclusive review has revealed anincidence of 4% to 35% in the United States. (6) Therelatively broad incidence range of TTTS likely reflectsdifferences in clinical criteria used to make the diagnosis.(3) Severe TTTS is reported to occur in 5.5% to17.5% ofcases. (7)

TTTS is detected ultrasonographically as fetal growthdiscordance and differences in amniotic sac size, theso-called “poly-oli” or twin oligohydramnios polyhy-dramnios syndrome picture. In severe TTTS, the donortwin becomes progressively hypovolemic and developsoliguria and oligohydramnios due to decreased renalperfusion as well as abnormal umbilical artery Dopplervelocimetry. The oligo-/anhydramnios of the donortwin may become so severe as to inhibit fetal movement.As the fetus becomes more closely enwrapped in itsamnion, it appears “stuck” to the uterine sidewall or itsplacenta (ie, “stuck twin” syndrome.) The recipient twinbecomes hypervolemic and hypertensive, which leads topolyuria and polyhydramnios. The recipient is character-istically larger, with cardiomegaly/visceromegaly (Fig.1), and may exhibit abnormal venous Doppler studyresults due to progressive ventricular hypertrophy andworsening diastolic compliance. Both twins are affectedadversely in TTTS. Hydrops fetalis may develop in eithertwin, but congestive failure is seen most commonly in therecipient. Left untreated, severe TTTS has an 80% to100% mortality rate, particularly if it is detected before20 weeks of gestation. (8)(9)

Prior to ultrasonography, the criteria for diagnosingTTTS were derived from neonatal experience with thecondition in which a greater than 5.0-g/dL (50.0-g/L)difference in neonatal hemoglobin value and greater than20% growth discordance was seen between the twins.However, these classic discrepancies between weight andhemoglobin values now are appreciated to occur in 25%or fewer of cases detected by ultrasonography. (9)(10)For example, hemoglobin discrepancy frequently is notobserved at midgestation, and severe TTTS may existprior to observing a 20% or greater fetal weight discor-dance. (9) As described previously, cases of intrauterinedeath of the donor twin may result in acute net bloodflow reversal, with the smaller, deceased twin suddenlybecoming plethoric and the former recipient becomingpale and anemic. (11) The severity of TTTS has beendescribed via a number of systems, notably the clinicalstages proffered by Quintero and associates (12) andlater modified by Harkness and Crombleholme. (9)

Pathogenesis of TTTSUltrasonographic, ex vivo and in vivo placental, mathe-matically derived vascular models and fetal and neonatalblood sample studies have revealed TTTS to be a com-plex and dynamic pathologic condition. In addition tothe inter-twin vascular connections, fetal biochemical,humoral, and functional adaptations also appear to bedeterminants of TTTS onset and progression. (1)(8)(9)(10)

Placental StructureTTTS is believed to develop because all DiMo twinsinitially share the chorion, the extraembryonic mesen-

Figure 1. Briefly formalin-fixed autopsy heart-lung blocspecimens from 1-day-old, 29-week gestational age twinswith history of TTTS. The donor twin’s (D) heart-lung bloc issmaller and paler than the recipient’s (R). The recipient’s hearthas been opened along the right ventricular outflow tract intothe pulmonary artery, and both blocs show some sectioning ofthe lungs. The marked ventriculomegaly and blunting of thecardiac apex are apparent. Modified from Faye-Petersen, et al(23) and used with permission.

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chyme. This layer differentiates into connective tissuestromal plugs that develop vascular cores through vascu-logenesis, which successively branch, via angiogenesis, toform the chorionic villous tree. Thus, although each twinhas its own umbilical cord vessels and acquires its ownconnections to and exerts its own influences on thedeveloping vascular territories within the placenta, DiMotwins theoretically have numerous “opportunities” forvascular connections (chorangiopagus vessels) to formand persist as sites of “third” circulation. (1) Indeed,several ex vivo injection studies have demonstrated suchanastomoses, (13) and studies using erythrocytes, pan-curonium, and microbubble contrast agents as markers,as well as color Doppler studies, have provided in vivoevidence. (10) At least 85%, if not essentially all DiMotwins, have sites of shared circulation. (10)(13)(14) Theshared villous tree has been shown to consist of direct,superficial anastomoses between the twins’ umbilicalcord branch vessels on the chorionic plate surface and“deep” sites, wherein the arterial ramifications from onetwin’s cord pierce the chorionic plate to supply a por-tion(s) of the villous tree that is drained by the venoussystem of its co-twin (Fig. 2). (Chorionic plate arterialand venous vessels are normally paired, but in a region ofshared villous tree in a DiMo placenta, the afferent arteryfrom the donor is unpaired, as is the efferent vein of therecipient.) The unidirectional “deep” arteriovenous(A-V) anastomoses within the placental cotyledons and

occurring at the villous capillarylevel have been implicated as themajor determinants of the imbal-anced shunting of blood occurringin TTTS. (1)(3)(5) The reader isreferred to a collective discussionamong major investigators ofTTTS, (15) but at least 80% ofcases of TTTS have been attributedto imbalances in the number, size,and direction of deep A-V anasto-moses.

Because of the putative majorrole of inter-twin anastomoses,most investigations of TTTS havebeen directed toward study of theDiMo placental vasculature. Stud-ies generally have identified a pau-city of anastomoses as a prominentrisk factor in the development ofTTTS. Paucity, especially of deepanastomoses, leads to fewerchances for volumetric balance in

cross-circulation between the twins. Larger numbers ofsuperficial chorionic anastomoses, particularly arterio-arterial (A-A) connections, appear to confer relative pro-tection against the development, early onset, or severityof TTTS. (9)(15)(16)(17)(18) However, the “protec-tive effect” of these A-A anastomoses remains somewhatcontroversial. Venovenous (V-V) connections comprisea lower percentage of anastomotic types found in DiMogestations and have been associated with poorer perinataloutcome. V-V anastomoses are seen in 20% of DiMoplacentas, A-A in 75%, and A-V in 70% by clinical andpathologic studies, but fetoscopic studies have shownthat 95% of anastomoses are A-V. (15)(19) However,some investigators have proposed that V-V anastomosesmay provide compensatory reversal of blood flow insome situations. (15) Presumably, as the recipient’s cen-tral venous pressure rises with hypervolemia and ensuingcongestive failure, the V-V anastomoses may be “protec-tive” to both twins by helping to alleviate right ventric-ular failure in the recipient and theoretically shuntingblood back to the venous system of the donor. Therelatively fewer numbers of V-V connections, in additionto their anatomy and lower pressure differential, may bedeterminants of how effectively they contribute to bal-ancing inter-twin blood flow.

Some researchers’ observations that the average num-bers of superficial vascular connections are not signifi-cantly different between gestations involving severe

Figure 2. Diagram of the anastomoses in a DiMo placenta. The right umbilical cord is fromthe donor twin (II) and the left umbilical cord from the recipient (I). The chorionic plateshows arterioarterial (A-A) and venovenous (V-V) superficial anastomoses. Normally, eacharterial branch of the chorionic plate is paired with a venous vessel. However, in theso-called “deep anastomosis,” an unpaired artery (blue for relatively low oxygenatedblood) from one twin (II in the diagram) supplies a portion of the chorionic villous treethat is drained by an unpaired vein from the co-twin (I in the diagram) (red to signifybetter oxygenated blood.)





TTTS and those that do not (14) and the fact that 80% to90% of DiMo twins do not develop TTTS has led otherinvestigators to propose that more than numerical differ-ences in anastomoses is involved in the pathogenesisTTTS. Recent evidence suggests that vascular diameterand resistance and the pattern of chorionic plate vascularbranching are important factors. Umur and associates,(17)(20) using a complex mathematical computermodel, determined that, for a given radius, an A-Aanastomosis has lower resistance than the equally sizedafferent artery of an A-V anastomosis, which might ex-plain the apparent protective effect of A-A anastomosesnoted in most studies of TTTS. By their calculations,blood flow could be balanced more efficaciously throughan A-A anastomosis than through oppositely directedA-V anastomoses, even though the pressure gradient inthe A-V anastomoses was greater.

De Paepe and colleagues (16) studied the chorionicplate branching pattern in DiMo placentas from gesta-tions without TTTS and those affected by severe TTTS.They found that gestations involving severe TTTS weremore likely to exhibit chorionic magistral or a mixedmagistral and diffuse pattern than unaffected gestations(60% versus 44%). The presence of a magistral pattern(a chorionic vascular pattern composed of relativelylarge-caliber, sparsely branching vessels that extendedfrom the cord insertion site to the placental peripherywithout significant diminution in diameter), even whenmixed with the more favorable disperse pattern (charac-terized by progressive and relatively uniform, dichoto-mous, fine branching of vessels from the cord insertionsite, with the smaller and smaller subdivisions extendingto the placental periphery), also was associated withhigher incidences of other placental anatomic featuresimplicated in the development of TTTS, such as unequaldistribution of vascular territory and marginal or vela-mentous cord insertions. In addition, donor twins weremore than twice as likely to have the magistral or mixedpattern as recipients, and when one or both twins had themagistral or mixed pattern, the average number of inter-twin anastomoses was fewer. These investigators sug-gested that the predominance of magistral and mixedpatterns in the donor twins’ placentas may be related tothe observations that magistral patterns in singleton pla-centas are associated with absent end-diastolic bloodflow (AEDF) in the umbilical arteries (UAs). AEDF hasbeen attributed to the effects of a smaller peripheralvascular tree that results in increased vascular resistanceto forward flow from the UAs. The low end-diastolicflow in the donor’s UAs combined with the magistral/mixed pattern might result in preferential routing of

blood flow through anastomoses to the recipient twin.Thus, evidence supplied by the various placental struc-tural studies of TTTS indicates vascular resistance, cross-sectional area, and other hemodynamic factors are con-tributing elements in the development, timing of clinicalonset, and severity of TTTS. (8)

Unequal sharing of the placental disc is an additionalrisk factor for the development of TTTS. (1)(18) How-ever, when and how disk inequality develops is unclear.The early developing chorionic villous tree may connectpreferentially to the vasculature of the umbilical cord ofone twin over that of the other. With unequal division ofthe inner cell mass, one embryo may develop a largerheart and, thereby, greater stroke volume and cardiacoutput, such that its perfusion of the developing villoustree initially is more robust. (1) However, others haveproposed that unequal sharing may reflect abnormalitiesof placentation. Not all twin pairs that have TTTS exhibitsignificant growth discordance, and there is evidence thatabnormalities of placentation may be relatively moreresponsible for the growth discordance in TTTS thanimbalances in inter-twin transfusion. (21) Approximately20% of cases of TTTS have concomitant evidence ofplacental insufficiency that usually, but not always, affectsthe donor twin. (22) The combination of placentationanomalies, flow inequalities, and fetal response may de-termine whether the donor’s placental territory appearsgrossly pale and bulky (Fig. 3) (with edematous large villicontaining increased Hofbauer [chorionic villous macro-phage] cells and nucleated fetal erythrocytes characteris-tic of fetal anemia) or whether it is pale and atrophic-appearing, with small villi. (3)(11)(23) Conversely, therecipient’s parenchymal territory usually is deep red-brown and firm due to villous congestion, but it also mayshow microscopic villous edema if the fetus is in conges-tive failure.

Marginal or velamentous cord insertions or singleumbilical artery are associated with increased risks of thedevelopment and severity of TTTS. (1)(11)(16)(24) Ofnote, although DiMo twins comprise 20% of twin gesta-tions, they have significantly increased rates of cordanomalies over diamniotic dichorionic twins, with morethan 50% of marginal cord insertions, more than 40% ofvelamentous cord insertions, and nearly 50% of all singleumbilical artery cases occurring in DiMo twins. (25)DiMo twins, therefore, are at constitutively increasedrisks for the underlying morbidity and mortality associ-ated with cord compression, cord accident with throm-bosis, and vessel rupture. Such cord events could com-pound any underlying risks of chorangiopagus, especially





Figure 3. A DiMo placenta from clinically diagnosed case of “stuck twin syndrome” wherein Twin 1 (single cord clamp) was clinicallydesignated as the donor Twin and Twin 2 (two cord clamps) as the recipient. A. The chorionic plate, with the donor twin side (D)on right showing a thin cord and the recipient side (R) on left having a thick, edematous cord segment. Note the large vessels thatcourse under the transparent dividing membrane. B. The chorionic plate in 3A after the amnion and dividing membrane have beenpeeled from its surface to expose the vessels. The donor, Twin 2 (D), has an unpaired arterial vessel that courses to a shared lobule(arrow) that is drained by a vein from the recipient (R), when the vessel is traced back proximally toward the cord insertion site ofTwin 1. Further examination revealed several other deep anastomoses of smaller caliber that had the “expected” donor-to-recipientarteriovenous (A-V) arrangement as well as some small “reversed” recipient-to-donor A-V-directed connections and somearterioarterial (A-A) anastomoses. C. An A-A anastomosis (white arrow) between a donor artery (yellow arrow) and a recipient artery(blue arrow). Images 3A–C underscore the importance of a thorough pathologic examination in TTTS cases because the netimbalance of the shunts ultimately contributes to the donor-recipient relationship. D. The maternal surface of a “classic” TTTS caseshows a congested recipient (R) and pale edematous donor side (D). E. The foramalin-fixed sections of the placenta in 3D (maternalsurface on left aspect of sections) shows the difference in the donor’s pale tissue and the recipient’s congested tissue. However, thedemarcation, although fairly distinct, is not a consistently transmural division, as might be suggested from the appearance of thematernal surface. Figures 3A-D are modified from Faye-Petersen, et al (23) and are used with permission.





for the donor twin. Donor twins are more likely to havevelamentous cord insertion than are recipients. (26)

Fetal Adaptive/Maladaptive and PlacentalResponses

The asymmetric, bidirectional inter-twin exchange ofblood and its biochemical components results in hemo-dynamic, osmotic, and physiologic changes in the fe-tuses. (1)(8)(9)(10) Hypovolemia and decreased renalblood flow in the donor may cause a number of renalstructural and functional aberrations, especially in severeTTTS, including renal tubular degeneration and cellularapoptosis, loss of glomeruli or reduction in tubular num-ber, and maldevelopmental progression to renal dysgen-esis. (27)(28) Renal hypoperfusion also has been linkedto activation of the renin-angiotensin system (RAS)(27)(29)(30) and elevated antidiuretic hormone concen-trations (31) in the donor. Donors have hyperplasia ofjuxtaglomerular apparatuses, with increased numbers ofrenin-secreting cells (27) and upregulation of renin syn-thesis, (29) which are presumed to represent adaptiveresponses to restore euvolemia. However, in severeTTTS, activation of the RAS and associated elevations inangiotensin II (AT II) likely result in AT II-mediatedfetal vasoconstriction that further compromises renalblood flow, leading to worsening oliguria and oligohy-dramnios. Increased fetal adrenal production of aldoste-rone may play a contributing role. (27)(29)(30)(31)Bajoria and colleagues (31) recently found that donors’plasma and amniotic fluid concentrations of vasopressinwere threefold higher than those of their co-twin recipi-ents. (DiMo twins that did not have TTTS had higherconcentrations than the recipients in TTTS, but theywere not discrepant or as elevated as the donors inTTTS.) Thus, good evidence suggests that the oligohy-dramnios of the donor twin is a consequence of poorrenal perfusion due to net hypovolemia, but it is exacer-bated by vasoconstriction, mediated by AT II/vasopressin. Fetal vasoconstriction also may reduce pla-cental blood flow to the villous tree, which maycontribute to growth restriction in the donor.(27)(29)(30)

In severe cases of TTTS, hypervolemic recipients haverenomegaly and glomerulomegaly consistent with in-creased renal blood flow, and immunohistochemicalstudies have revealed they have downregulation of theRAS, with markedly reduced numbers of renin-secretingcells and renin synthesis. (27)(29)(30) However, theyhave paradoxically high concentrations of renin and al-dosterone, and the cardiomegaly, cardiomyopathy, hy-pertension, and nephrosclerosis seen in recipients in

TTTS are insufficiently explained by hypervolemia alone.Such observations are supportive evidence for transfer ofthese and possibly other vasoactive effectors from thedonor to the recipient across placental anastomoses. Thehemorrhagic necrosis and microangiopathic lesions seenin kidneys from recipients in severe TTTS also may berelated to transanastomotic passage of hormones fromthe donor. (30)(32) Low concentrations of antidiuretichormone in the recipient, together with elevated reninconcentrations secreted by the donor, are likely respon-sible for worsening hypervolemia and polyuria/polyhydramnios in recipients. Maternal sequelae of fetalelevations in vasoactive substances have been appreciatedrecently. Elevated fetal renin-AT II values have beenassociated with maternal pseudoprimary hyperaldoste-ronism, (33) and it is possible that these contribute tochanges in maternal perfusion of the placental bed.

In addition to anastomotic transfer of vasoactive me-diators, increased cardiac synthesis and secretion of na-triuretic peptides (NPs) have been linked to the progres-sion of TTTS. NPs are a family of biochemical mediatorsthat normally regulate blood pressure and body fluidhomeostasis through their diuretic, natriuretic, and va-sodilatory effects as well exerting antiproliferative effectson cardiovascular/mesenchymal tissue. Exploration oftheir role in the pathogenesis of adult cardiac hypertro-phy and cardiomyopathy has led to greater appreciationof their importance in normal embryofetal developmentand their role in cardiomyopathy in the recipient twin inTTTS. In the fetus, in contrast to the adult, both atrialnatriuretic peptide (ANP) and brain natriuretic peptide(BNP) hormones are normally at high circulating con-centrations and are expressed at high concentrations inthe ventricles (in the normal adult, they are in expressedat low concentrations in cardiac atria and ventricles,respectively.) Their release is stimulated primarily byincreased myocardial stretch and volume overload, hy-perosmolality, and hypoxia, and vasoconstrictors, such asAT II, vasopressin, and endothelin-1 (ET-1), have beenshown to result in their increased expression and secre-tion. ANPs and BNPs appear to be integral to embryonicfetal salt and water and blood pressure regulation, andthe peptide system is likely functional by midgestation.ANP and BNP also appear to be important mediators ofcardiogenesis because of their inhibitory effects on myo-cardial and fibroblast cell proliferation. Their effects onfetal aldosterone concentrations are unknown, but theysuppress aldosterone synthesis in the adult. A third NP,c-type natriuretic peptide (CNP), which is found in adultgenitourinary, pituitary, and brain tissues, is not pro-duced in any significant quantity in the fetal or adult





heart, although it is secreted by the placenta. Placentalproduction of NPs (ANP, BNP, CNP) affect vasorelax-ation in the fetoplacental vasculature and likely helpregulate blood supply to and within the fetus.

ANP and BNP both bind to natriuretic receptorNPR-A, a guanyl cyclase-linked receptor, which leads togeneration of cytosine-GMP and the cascade that resultsin their physiologic effects. (34)

Bajoria and colleagues (35)(36) demonstrated thatrecipient twins in TTTS have higher concentrations ofANP, BNP, and ET-1 than their co-twin donors orDiMo twins without TTTS and that high concentrationsof BNP and ET-1 are particularly correlated with cardiacdysfunction in the recipient. They suggested that thesecompounds might be used as early markers of cardiaccompromise. It is plausible that the immaturity of thefetal kidney and its inability to concentrate urine may beexacerbated by the vasodilatory and diuretic effects ofBNP and ANP released due to hypervolemia and con-tribute to polyuria/polyhydramnios or be compoundedby BNP stimulation due to AT II transferred from thedonor. Increased ANP concentrations in blood and am-niotic fluid have been detected in recipients in TTTS,greater than donor twin’s and uncomplicated DiMo twinpair’s values. Increases in ANP also are related directly toincreases in amniotic fluid volumes, and markedly in-creased immunostaining for ANP localizes predomi-nantly to the heart and cytoplasm of the distal convo-luted tubules of the kidneys of recipients when comparedwith measurements for donor twins. These data aresupportive evidence that polyhydramnios in the recipienttwin occurs as a consequence of ANP-mediated increasesin fetal urine output due to ANP expression in bothcardiac and renal tissues. (37)

Cardiac hypertrophy with cardiac dilatation is seen inrecipients in TTTS and likely is due to the increasedcardiac preload and increased afterload pressures due tohypertension. (30)(38) Of note, ventricular hypertrophypredominates and dilatation is comparatively “mild,”with right ventricular compromise preceding and gener-ally exceeding that of the left ventricle. (9) Although theright ventricle is the primary “workhorse” of the fetalheart, and fetal myocardium can proliferate, other devel-opmental factors likely contribute to the myocardial mu-ral thickening detected by ultrasonography. Fetal myo-cardium is “stiffer” than the adult heart. The fetalmyocardium has a greater percentage of noncontractileelements (60% versus 30% in the mature heart) andrelatively delayed removal of calcium from troponin C,and the ventricles have a shorter phase of early passivediastolic filling and a greater reliance on atrial contrac-

tion. Fetal lamb studies have shown that after 4 to 5 mmHg, further atrial preload does not result in increasedstoke volume. Thus, the fetal heart is inherently andmechanically less efficient, is less able to increase strokevolume, and displays impaired relaxation. (39) Theseeffects may represent, in part, disruption of the NPsystem, which has been shown to be NP receptor-dependent in murine models. NP receptor-deficient,Npr1�/� knockout mice develop hypertension, cardiachypertrophy, and fibrosis. The absence of the receptoreffectively inhibits vasorelaxation despite elevated con-centrations of BNP and ANP. Moreover, cardiac hyper-trophy can result independently of the presence of hyper-tension because the lack of receptor does not permitinhibition of myocardial proliferation/enlargement andfibroplasia.

The murine studies also may help to explain whycardiac anomalies are more common in recipient thandonor survivors. Recipient twins are at increased risk forright ventricular outflow tract obstruction and pulmo-nary valvar stenosis/atresia with intact ventricular sep-tum. (9) The progressive hypertrophy, reduced systolicfunction, and tricuspid valvar insufficiency lead to pro-gressive decline in flow across the pulmonary valve. In acase in which the infant underwent surgical repair, thetrileaflet semilunar valvar anatomy was identified as nor-mal except for adhesions of the coapted leaflets. Thus,the pulmonary valvar stenosis/atresia in recipient twinsseems to represent a unique form of “acquired congenitalheart disease” and not a primary malformation. (9)ANP/BNP signaling interruption may play a significantrole in the generation of cardiac hypertrophy and dys-function. (34) The right and left ventricular myocardiumhave embryologic differences, and the number of NPreceptors in the right ventricle may be inherently lower;once proliferation and hypertrophy ensue, the right ven-tricle may become progressively more vulnerable to theeffects of preload, afterload, and pressors.

Although cardiac dysfunction is more common andmore dramatic in recipients, decreased cardiac perfor-mance and injury also may occur in donor twins in TTTS.(8)(9) Protracted increase in cardiac demands and energyexpenditure, due to continued transfusion of the co-twin, and hypoxemia and acidemia, due to the anemiaand probable shrinking efficiency of placental function,contribute to reduced cardiac function and growth re-striction in the donor. (8) Umbilical arterial end-diastolicforward blood flow diminishes to become absent(AEDF). (8)(10)(21)(38)(40) Hydrops from high-output cardiac failure can ensue in the donor due to lossof oncotic pressure from chronic transfusion (8) and





hypoproteinemia due to passive hepatic congestion andreduced hepatic synthesis that reflects reduced blooddelivery to the liver (due to splanchnic vasoconstrictionand relative preservation of blood shunting through theductus venosus with effective bypass of the liver) andplacental insufficiency with reduced nutritional supply.

Other Molecular Mechanisms Implicated inTTTSMyriad other factors have been identified as determi-nants in normal and abnormal placental development insingleton gestations, and it is likely that aberrations inexpression, timing of onset, and duration of expressionof these angiogenic and trophotropic factors potentiallyare involved in the pathogenesis of TTTS. Several appearto have implications for the asymmetric placental andchorionic vascular branch pattern development, placen-tation, and fetal growth restriction in the donor twin.Detailed discussion of these complex factors is beyondthe scope of this review, but chorionic vascular prolifer-ation, branching, and lengthening are affected by oxygentension and hormonal factors that exist in the maternalspace, (1)(5)(41)(42) relative values of promoters ofangiogenesis (ie, vascular endothelial growth factorA and placental growth factor), (43)(44)(45) popula-tions and distributions of receptors to these growthfactors, relative concentrations of trophoblast-producedand milieu-associated antiangiogenic determinants,(44)(45)(46) and effects of local mediators such as nitricoxide. (16)(47) The roles of insulin-like growth factorsand receptors, (48)(49)(50) fetally produced hormonessuch as leptin, (48)(50)(51)(52) and placental inflamma-tory mediators such as interleukin-6, -8, and -10 (5)(49)likely will be determined to have a role in the pathogen-esis of abnormalities associated with the vasculature,placentation, and growth of the placenta and fetal twinpair.

SummaryTTTS is a complex condition that results from circula-tory imbalances due to placental anastomoses betweenDiMo twins. Its date of onset, rate of progression, andseverity are multifactorial and reflect numbers and typesof anastomoses, unequal sharing of the placenta, trans-fusion of vasoactive mediators from the donor, abnormalexpression of hormones that affect cardiac function in therecipient, and the effects of fetoplacental vascular resis-tance. Many of the deleterious effects of TTTS haveimplications for the necessity for and responsiveness tomedical therapies for neonates born of these complicatedgestations. The intrauterine environment of TTTS, with

its circulating mediators and shifts in blood shuntedbetween the twins, ultimately can affect cardiac, renal,and hepatic function of the twins. Greater understandingof the pathogenesis of TTTS can help neonatologistsexplain the sometime confusing findings in the donorand recipient twins.

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NeoReviews QUIZ

1. Chronic twin-to-twin transfusion syndrome (TTTS) is a condition characterized by a sustained imbalance ofblood volume transfused between twins, with one twin becoming a donor and the other twin becoming arecipient of the transfusion. Of the following, the most accurate statement regarding chronic TTTS is that:

A. Arterioarterial anastomoses in the placenta are associated with poorer perinatal outcome thanarteriovenous anastomoses.

B. Chronic TTTS is almost exclusively restricted to twins with diamniotic monochorionic placentations.C. Marginal or velamentous umbilical cord insertions or a single umbilical artery lessen the severity of

TTTS.D. Recipient twins are more likely than donor twins to have a chorionic magistral blood vessel pattern.E. Recipient twins are more susceptible than donor twins to fetal entrapment in the amnion (“stuck twin

syndrome”).

2. In chronic TTTS, the asymmetric inter-twin exchange of blood and its biochemical components results inhemodynamic, osmotic, and pathophysiologic changes in the fetuses. Of the following, the hormone mostlikely to be upregulated in the recipient twin in chronic TTTS is:

A. Aldosterone.B. Angiotensin II.C. Arginine-vasopressin.D. Atrial natriuretic peptide.E. Renin.





DOI: 10.1542/neo.9-9-e3702008;9;e370Neoreviews

Ona M. Faye-Petersen and Timothy M. CrombleholmeTwin-to-Twin Transfusion Syndrome : Part 1. Types and Pathogenesis

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