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The TwinTwinTransfusion SyndromeVENU JAIN, MD, PhD andNICHOLAS M. FISK, PhD, FRCOGCenter for Fetal Care, Queen Charlottes and Chelsea Hospital,Institute of Reproductive and Developmental Biology, ImperialCollege London, London, UK
Twintwin transfusion syndrome (TTTS) isa complex cardiovascular disease affectingmonochorionic (MC) twin pregnancies. Al-though well characterized clinically, its etio-pathogenesis remains poorly understood.TTTS, which affects genetically-identicalstructurally normal fetuses, primarily in-volves unbalanced transfusion of bloodfrom a net donor to a net recipient along oneor more placental arteriovenous anastomo-ses in absence of adequate compensatorycounter-transfusion along bi-directional su-perficial anastomoses. The resultant fetalhemodynamic changes, and their associatedbiochemical/humoral adaptations are re-sponsible for the disparate phenotypic fea-tures found in the donor and recipient twins.
TTTS is arguably the oldest medical con-dition recorded. As described in the Bible(Genesis 25:21-32), it appears that the twinsof Isaac and Rebekah who struggled to-gether within her were afflicted with TTTS.The first born, Esau, who came out red,
was faint, and at the point to die, mayhave been a recipient. Today, TTTS remainsone of the greatest challenges in modern fe-tal medicine for several reasons. Firstly, un-treated, it is associated with extremely highperinatal mortality ( 80%) and morbidity.Secondly, not one but two babies are af-fected. Third, unlike many other fetal pa-thologies, these babies are entirely normalstructurally, thus with good potential for in-tact survival. Finally, the problem is an ana-tomic one in the placenta, which should, atleast theoretically, be amenable to surgicalcure. Because disease severity varies fromsubclinical to life threatening, and becauseof the multitude of treatment options avail-able, clinical management of TTTS remainschallenging, despite considerable recent ad-vances.
Clinical FeaturesTTTS occurs in approximately 15% of MCdiamniotic twins, affecting approximately 1in 1600 pregnancies overall.1 It is not knownto occur in monoamniotic twins. TTTS canalso occur within MC twin pairs in tripletand quadruplet pregnancies. TTTS is usu-ally diagnosed on serial ultrasound indicated
Correspondence: Dr. Venu Jain, Clinical Lecturer in Ob-stetrics and Gynaecology, Institute of Reproductive &Developmental Biology, Imperial College London, Ham-mersmith Campus, Du Cane Road, London W12 0NN,United Kingdom. E-mail: [email protected]
CLINICAL OBSTETRICS AND GYNECOLOGYVolume 47, Number 1, 181202 2004, Lippincott Williams & Wilkins, Inc.
CLINICAL OBSTETRICS AND GYNECOLOGY / VOLUME 47 / NUMBER 1 / MARCH 2004
routinely in MC twins albeit may rarely pres-ent with polyhydramnios, preterm labor orpreterm premature rupture of membranes(PPROM). Sonographic features of TTTSusually manifest between 15 and 25 weeks,although early 3rd trimester presentationsstill occur. The net donor develops featuresof anemia/hypovolemia including oliguria,oligohydramnios, growth restriction, abnor-mal umbilical artery Dopplers and circula-tory redistribution (Fig. 1). Anhydramniosin the donor amniotic sac can lead to thesonographic appearance of a stuck twin.In contrast, the net recipient shows signs ofhypervolemia, including polyuria, polyhy-dramnios, visceromegaly, abnormal venousDopplers, cardiac enlargement/failure, and,in extreme cases, hydrops (Fig. 1).
Before ultrasound, TTTS was diagnosedin MC pregnancies based on growth discor-dance of 20% associated with a discor-dant fetal/neonatal hemoglobin of 5 g/dl.However these diagnostic criteria are oftensatisfied by discordant growth restrictionand are now considered unreliable forTTTS. Paired fetal blood sampling hasshown hemoglobin discordance of 5 g/dlin only 25% of 36 cases of TTTS, with amean hemoglobin difference of 3.6 g/dl.2
Discordant fetal growth (birth weight differ-ence 20%) occurs as commonly in dicho-rionic as in MC twins.3
TTTS is now defined as presentation inthe mid - t r imes t e r wi th the o l igo -polyhydramnios sequence, the deepest ver-tical pool in the donor being 2 cm and inthe recipient 8 cm. Other supportive fea-tures are a small or non-visible bladder andabnormal umbilical artery Doppler (absentor reversed end-diastolic frequencies[AEDF/REDF]) in the donor in associationwith a large bladder, cardiac hypertrophy,abnormal umbilical vein/ductus venosusDopplers and hydrops in the recipient (Fig.1). Discordant intrauterine growth restric-tion (IUGR) can mimic the donors pheno-type but should not be associated with therecipients phenotypic features in the co-twin.
Pathophysiology of TTTS
ANATOMIC BASISEx-vivo dye-injection studies have shownthat almost all MC placentae contain vascu-lar anastomoses (Fig. 2).4 Thus, intertwintransfusion is the norm in MC pregnancies.This has been confirmed by in-vivo studiesexamining markers including erythrocytes,pancuronium, and microbubble contrastagents injected in one twin for passage intothe co-twin.5,6
There are three types of interplacentalanastomosesarterio-arterial (AAA),veno-venous (VVA) and arterio-venous(AVA). AAAs (Fig. 2) and VVAs are super-ficial anastomoses that course entirely alongthe chorionic plate. These are capable of bi-directional flow depending on alterations inotherwise similar baseline hydrostatic pres-sures. In contrast, deep AVAs (Fig. 2) medi-ate unidirectional flow from one twin to theother, but are not strictly anastomoses asthey do not bypass the capillary circulation.Here, the artery from one twin enters the pla-cental cotyledon from the chorionic plateand forms the usual stem villous capillarybed, but the corresponding vein thatemerges close to the feeding artery drains tothe co-twin. AVAs are present in almost allMC placentae, AAAs in most and VVAs inonly approximately 25%.7,8
Although Schatz suggested more than acentury ago that TTTS is caused by unbal-anced intertwin transfusion, the anastomoticpatterns responsible for such imbalancehave proved difficult to unravel.9 We havehypothesized, that anastomoses arise in theembryological stage of connection of em-bryonic and extra-embryonic circulations,and that during placental growth, there israndom loss of these anastomoses, andTTTS develops when this results in asym-metric flow resistance to net interplacentaltransfusion.10 Deep anastomoses ie, AVAswith net unidirectional blood flow in the ab-sence of compensatory bidirectional super-ficial anastomoses ie, AAAs and VVAswould result in an unbalanced intertwin
182 Jain and Fisk
FIGURE 1. Ultrasound and Doppler findings in twintwin transfusionsyndrome (TTTS). Features of stage II TTTS include oligohydramnios-polyhydramnios sequence with growth discordance and nonvisualization ofdonor bladder (Panel A). Manifestations of hemodynamic compromise instage III TTTS include reversed end-diastolic frequencies (REDF) in um-bilical artery of donor twin (Panel B), and pulsatile flow in umbilical vein(Panel C), reversed flow in ductus venosus (Panel D) and marked tricuspidregurgitation (Panel E) in recipient. Worsening cardiovascular dynamics inrecipient result in fetal hydrops ie, stage IV (Panel F).
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transfusion, mediating a state of hypovole-mia in the donor and hypervolemia in the re-cipient. Initial ex-vivo injection studies con-firmed that TTTS placentae had more deepthan superficial anastomoses compared withMC controls.4,7 Endoscopic studies, thoughlacking histopathological confirmation,confirm injection study evidence that themajority of TTTS placentae show a highernumber of AVAs from donor to recipientthan in the opposite direction.11,12 Throm-bosis of a previously compensatory reverse-directed AVA from recipient to donor canlead to rapid onset of TTTS in a previouslyunaffected pregnancy.12 Notwithstandingan endoscopic report of TTTS with no deepanastomoses,13 ex-vivo studies show thatAVAs are present in all TTTS placentae asopposed to 84% of controls.8 In addition,78% pregnancies with one or more AVAs inthe absence of AAAs develop TTTS.8 Thelargest ex-vivo placental injection study hasshown that AAAs are less frequent in TTTS(24% versus 84% in controls) whereas thefrequency of AVAs and the rarer VVAs issimilar.14 In support of this, computer mod-eling has shown that unidirectional, or morelikely, asymmetrical bidirectional intertwintransfusion results in hemodynamic, os-motic and physiological changes consistentwith the clinical features of TTTS.15,16
AAAs have a greater potential for hemo-dynamic counter balancing than VVAs byvirtue of their higher pressure differential.
The protective role of AAAs in MC twinpregnancies has been validated by imagingstudies.14,17 AAAs can be ascertained ante-natally by color Doppler from as early as 12weeks gestation.18 Absence of AAAs is as-sociated with an increased risk of TTTS(61% versus 15%, odds ratio 8.6).14 Com-puter modeling studies confirm that AAAsconfer greater protection against TTTS thanoppositely-directed AVAs.19
Aberrant placentation and velamentouscord insertion have also been implicated inthe development of TTTS.20,21 However, astudy of 90 MC placentae showed similar in-cidence of velamentous cord insertion inTTTS placentae (53%) and in MC controls(52%).21a However histology shows that thedonor territory, although showing slightlyedematous villi with small vessels, is moresimilar to a normal than to a growth re-stricted singleton placenta, while the recipi-ent placenta appears postmature, with a thintrophoblast layer and numerous vasculosyn-cytial membranes.22
CARDIOVASCULARPATHOPHYSIOLOGYAlthough anastomotic transfusion createsthe primary hemodynamic discordance,adaptive/maladaptive secondary fetal physi-ological or placental responses contributetoward disease manifestations.
Hypovolemia in the donor results in
FIGURE 2. Vascular anastomoses in atwin placenta from a monochorionic-diamniotic pregnancy. Vascular castinghas been used to delineate the vessels andtheir anastomoses. The white arrow indi-cates an arteriovenous anastomosis(AVA) with the transfusional directionbeing from the artery on the left to thevein on the right. The black arrow pointsto an arterioarterial anastomosis (AAA).
184 Jain and Fisk
growth restriction, redistribution of bloodflow, decreased renal perfusion and oligo-hydramnios. In advanced disease, increas-ing fetoplacental resistance manifests asAEDF or REDF. In the donor kidney, de-generative changes and decreased mass ofthe renal tubules may progress to renal tubu-lar dysgenesis.23 Decreased glomerular fil-tration and renal perfusion in the donor maybe responsible for a renal defect which ismore likely a primary developmental de-fect rather than secondary to ischemia.23
Apoptosis-mediated loss of proximal andmedullary tubules is thought to be a precur-sor of more diffuse renal tubular atophy.24
In the recipient, phenotypic features havelargely been attributed to hypervolemia.High atrial natriuretic peptide (ANP), se-creted in response to fluid overload, alongwith concomitant suppression of antidi-uretic hormone (ADH) mediates the asso-ciated polyuria and polyhydramnios.25
Amniotic pressure is raised in the polyhy-dramniotic sac and its amelioration by am-nioreduction is associated with increaseduterine artery blood flow and improved fetalacidbase status.2628 Hypervolemia also el-evates cardiac preload. Findings of hyper-tension in the recipient indicate that elevatedafterload may also contribute to cardiovas-cular dysfunction.29 Implicated in this is en-dothelin, levels of which are raised in the re-cipient compared with the donor.30 Cardiacfailure is evident initially by venous Dopplerchanges including AEDF/REDF in the duc-tus venosus, pulsatile flow in the umbilicalvein and tricuspid regurgitation, and later byfetal hydrops (Fig. 1). Cardiac hypertrophysecondary to raised afterload sometimes re-sults in a functional right ventricular outflowobstruction.31,32 Recipient kidneys are en-larged, congested and show hemorrhagic in-farction, with glomerular and arterialchanges resembling polycythemia and hy-pertension.33
Disturbances of the renin-angiotensin-aldosterone system (RAS) have been de-scribed in the donor as well as the recipi-ent.33,34 There is overexpression of renin in
donor kidneys, presumably as a result ofchronic renal hypoperfusion. Though possi-bly beneficial for adaptation to hypovole-mia, the associated increase in angiotensin IIcan worsen the donors fetoplacental vaso-constriction thereby decreasing renal andplacental blood flow, promoting growth re-striction, and worsening oliguria and oligo-hydramnios. This could be further aggra-vated by increased aldosterone productionby the fetal adrenal glands. Interestingly, hy-peraldosteronism has been noted in womenwith TTTS-affected pregnancies. Renin ex-pression is significantly reduced in the re-cipients, probably in response to hypervol-emia.33,34 However, paradoxical RAS acti-vation due to transfer of effectors such asrenin and/or angiotensin II from the donorthrough placental shunts could explain fetalhypertension and cardiomyopathy in the re-cipient.33
Clinical CourseAll MC pregnancies should be scanned ev-ery 2 to 4 weeks for early detection ofgrowth and amniotic fluid discordance,Doppler abnormalities and other features ofTTTS. When minor amniotic fluid discor-dance is noted, scans should be done morefrequently. Fetal echocardiography is indi-cated in all MC twins in view of an increasedincidence of cardiac anomalies, (3.8% v0.6% in singletons).32
Retrospective studies show that the me-dian gestational age at diagnosis of TTTS isaround 21 weeks and 29 weeks at deliv-ery.35,36 Preterm labor or PPROM occursecondary to raised amniotic pressure withpolyhydramnios, but may also be a conse-quence of therapeutic procedures.37 Pretermlabor or PPROM is managed in the usualfashion, and preterm delivery is associatedwith the usual complications of prematurity.However, preterm TTTS babies, especially 28 weeks, do much worse neonatally thantheir singleton or non-TTTS twin counter-parts. Cardiac dysfunction in the recipient is
TwinTwin Transfusion 185
the main additional problem, while renaldysfunction and growth restriction are majorissues for the donor.
Untreated, TTTS is associated with aperinatal loss rate 80% and frequent long-term morbidity in survivors especially neu-rologic sequelae.1,38 The donor is morelikely to die than the recipient, and neonataldeaths outnumber fetal deaths by 2:1, al-though the latter may be attributed to lategestational age at presentation in older se-ries.3941 Where there are arterial Dopplerabnormalities ie, AEDF/REDF in the donorumbilical artery or venous abnormalities inthe recipient, perinatal death of one or bothbabies occurs in 65% of cases.17 Retrospec-tive analysis of 136 fetuses diagnosed withTTTS 28 weeks and managed expectantlyrevealed an overall survival of 27% withneurologic impairment in 25% of survi-vors.42
Death of one twin in utero complicatesabout 30% of affected pregnancies.35,40,43,44
This may result in improvement of the con-dition in the surviving co-twin with resolu-tion of TTTS due to cessation of the inter-twin transfusion. However, there are sub-stantial risks to the remaining twin includinga 25% risk of ischemic brain injury or renallesions in survivors and a comparable risk ofimmediate co-twin fetal death.45,46 Fetalblood sampling studies support the theorythat the increased risk of death or neurologicinjury in the surviving MC co-twins is due toexsanguinatory intertwin transfusion fromthe surviving twin into the dead twins vas-cular compartment.44 This seems morelikely after recipient death in utero, but para-doxical exsanguination of the recipient intothe dead donor has also been reported.47 Theoutcome for the survivor is poorer in thepresence of an AAA, presumably because ofmore rapid mediation of agonal intertwintransfusion.48 Notwithstanding this, AAAsare less frequent in advanced stage TTTS,and are usually associated with high doublesurvival in Stage IIII disease.49
Prediction of TTTSTwins presenting with severe TTTS in themid-trimester may have hemodynamic im-balance from the first trimester manifest asdiscordant increased nuchal transluscency(NT) at 10 to 14 weeks.10,50 This is of rel-evance as NT is the primary screening testfor aneuploidy in multiple pregnancies. Se-bire et al found that 32% of MC pregnancieswith increased NT subsequently developedTTTS (likelihood ratio 3.5, 95% CI 1.96.2)although only 28% of cases were pre-dicted.50
Another finding associated with laterTTTS is folding of the intertwin membraneat 1517 weeks. This is seen in 32% of MCpregnancies, 43% of which subsequentlydevelop TTTS (likelihood ratio 4.2, 95% CI3.06.0).50 However the utility of this sub-jective finding in predicting TTTS that re-mains debatable.
Doppler studies of placental anastomoseshave shown that TTTS develops in 15% ofpatients with an AAA versus 61% withoutan AAA (OR 8.6).14 Conversely however,25%30% of TTTS placentae still have anAAA, although, when TTTS develops inthe presence of AAAs, it is associated withconsiderably higher perinatal survival.14
AAAs can be detected after 18 weeks us-ing spectral and color Doppler with an 85%sensitivity and 97% specificity, thoughdetection as early as 11 weeks is possible.14
Typically, the presence of an AAA isrevealed by a bidirectional speckled pat-tern on color or power Doppler (Fig. 3, panelA).14,18 In a series of 105 patients with MCpregnancies, 68 (65%) had an AAA con-firmed by ex-vivo injection studies, 59(56%) of which were identified in vivo byDoppler.14 Computer modeling supportsvarying bidirectional flow in the AAA,the periodicity of which has been shownto be a function of the difference in twinsheart rates (Fig. 3, panel B).15 Further,this bidirectional pattern transforms tounidirectional flow in the event of intrauter-
186 Jain and Fisk
ine demise of one twin.51 Interestingly,cyclical changes in umbilical arterial flowhave been seen in growth restricted MCtwins (in the absence of TTTS), these aresecondary to retrograde transmission froma large AAA.52 Factors that facilitate detec-tion of AAAs are an anterior placenta, largerdiameter AAAs, gestational age 20 to 30weeks, and serial scanning.14 Therefore,absence of an AAA is a good predictor ofdevelopment of TTTS, and more signifi-cantly, of severe TTTS associated with poorprognosis. Attempts should be made to iden-tify AAAs on serial ultrasound between 14and 28 weeks both to predict prognosisas well as to select appropriate manage-ment.14,18,52 The main clinical issue withthis test is distinguishing a true negative re-sult from a false negative due to early gesta-tion.
StagingQuintero et al developed an intuitive stagingsystem to categorize disease severity.53
Stages I to V are based on progressively-worsening clinical features: stage I,oligo/polyhydramnios sequence only withbladder visualized in the donor twin; stageII, bladder not visualized in donor; stage III,critically abnormal Dopplers (AEDF orREDF in the donor umbilical artery, or re-verse flow in the ductus venosus or pulsatileflow in the umbilical vein in the recipient);stage IV, hydrops in recipient; stage V, de-mise of one or both twins (Fig.1). This stag-ing system for TTTS was designed to assistwith determination of prognosis, and tostandardize comparison of treatment re-sults.53,54 However, attempts to validatestaging by outcome may be distorted by thetreatment paradox ie, improving outcomes
FIGURE 3. The characteristic peri-odic bidirectional flow waveform of anarterioarterial anastomosis (AAA). PanelA: Demonstration of an AAA usingDoppler sonography on the chorionicplate. The high frequency alternating bi-directional flow across this anastomosisproduces a speckled pattern on colorDoppler. Panel B: Computer modelingusing two fetal circulations in a model ofmonochorionic diamniotic pregnancyconnected by an AAA as shown in theupper right corner. The net direction andamount of flow across this anastomosis(lower trace) is determined by superim-position of oppositely directed flowsthrough the abdominal aortae (uppertrace) and umbilical arteries (middletrace) of the two twins, being a functionof the difference between the two heartrates (10% in this case). (From Taylor etal. Mapping the monochorionic equator-the new frontier. Ultrasound Obstet Gy-necol 1999;14:372374. By permissionof John Wiley & Sons, Inc.)
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in presence of worse disease. In a recentstage-dependent survival analysis of 52 con-secutive cases with a median gestation atpresentation of 21 weeks and 29 weeks atdelivery, severe TTTS (stage III) was pres-ent in 63% at presentation.55 Excludingelective terminations and stage V disease,45% of TTTS cases progressed to a more ad-vanced stage while 18% regressed to a lesserstage. Of note, stage II was often temporary,with 20% of cases progressing but 60% re-gressing to stage I. Notwithstanding this,78% of cases were at least stage III at sometime during the pregnancy. Survival rateswere 58%, 60%, 42% and 43% for stagesIIV at presentation, respectively, with nosignificant influence of stage on survival.On the other hand, in terms of worst everstage, survival was 75%, 67%, 52% and43% for stages IIV respectively. Survivalwas poorer where stage increased (27% ver-sus 94% when stage decreased). Thus, stag-ing may be more useful for monitoring dis-ease progression than for absolute risk as-sessment.55
At Queen Charlottes and Chelsea Hospi-tal we now use a modified staging systemthat incorporates the antenatal finding of anAAA indicating improved prognosis intothe TTTS stage. If an AAA(s) is noted, stageis post-scripted with an a as opposed to ab when none is detected. Thus, stage IIIdisease is sub-staged as IIIa in presence ofan AAA and IIIb in its absence. In addition,IIIb may be downstaged to IIIa if subsequentscanning elicits the presence of an AAA. Inan analysis of 96 TTTS pregnancies, overallsurvival was better in the presence of anAAA on antenatal ultrasound (83%) than intheir absence (52%).49 Presence of an AAAconferred a stage-dependent survival advan-tage to fetuses in stages I-III (Overall sur-vival (stage at treatment): Ia 100%, Ib 63%,IIa 100%, IIb 59%, IIIa 83%, IIIb 44%, IVa25%, IVb 50%).49 Interestingly, survival isactually better in stage IIIa compared withIb. Thus, our AAA modification of theQuintero classification improves prognostic
stratification and seems an important vari-able in treatment selection.
ComplicationsIn addition to the morbidity associated withTTTS discussed above, some problemsmerit further discussion.
NEUROLOGICAL COMPLICATIONSTTTS is associated with an increased risk ofneurologic sequelae. There is a paucity oflong term follow up neurodevelopmentalcohort studies. Overall, there is an approxi-mate 15% incidence of long-term neuro-logic sequelae in survivors.35,38,5659 Ofthese, just over half involve cerebralpalsy.35,38,54,56,58,60 Neurologic morbidityis the result of antenatal insults as well asthe sequelae of preterm birth such as peri-ventricular leukomalacia (PVL) and intra-ventricular hemorrhage. The likely patho-genesis of antenatally-acquired lesions isischemia attributable to hemodynamic im-balance via placental vascular anastomoses.Polycythemia and vascular stasis in the re-cipient and anemia and hypotension in thedonor are potential mechanisms for neuro-logic insults. Most series show equal dis-tribution of neurologic lesions between do-nors and recipients.43,56,61,62 Death of onetwin is associated with an increased risk ofneurologic sequelae in the surviving co-twin.36,41,44,53 Despite initial claims of a de-crease in neurologic sequelae after lasertreatment, recent studies have not been ableto confirm lower sequelae with any treat-ment modality, as discussed in the manage-ment section.
Neurologic sequelae have sometimesbeen inferred from abnormalities on ante-natal or early postnatal imaging studies.However an ultrasound abnormality doesnot necessarily equate with neurologic se-quelae. On postnatal cranial ultrasound,29% of TTTS survivors have abnormali-ties.35,36,38,43,60,61,63 In 12% of survivors,these findings are PVL of antenatal ori-gin.36,60 However, most ultrasound lesionsare minor, consisting of mild ventriculo-
188 Jain and Fisk
megaly, subependymal pseudocysts, smallwhite matter cysts and basal ganglia echo-genicity or lenticulostriate vasculopathy.36,61
Antenatally-acquired lesions should be dif-ferentiated from postnatally acquired oneswhich include hemorrhages and PVL evi-dent on delayed neonatal imaging.63 Sur-prisingly, in the absence of TTTS, 23% ofMC twin survivors also have abnormal post-natal ultrasound findings.62 In addition,postnatal ultrasound studies in term infantsshow an incidence of minor lesions as highas 27%30%.64,65 However, none of theseinfants had cerebral palsy or major develop-mental delay.64,65 The varying incidence ofultrasound abnormalities in TTTS affectedsurvivors and control term infants in variousstudies is also likely to be influenced by thesensitivity of the imaging technique used indifferent studies.
CARDIOVASCULAR COMPLICATIONSAlthough MC twins have a six-fold in-creased risk of congenital cardiac anoma-lies, this is even higher in TTTS (6.9% withversus 2.3% MC twins without TTTS).32
TTTS survivors are at increased risk of bothcongenital and acquired cardiovascular le-sions.31,32 All recipients manifest variabledegrees of biventricular hypertrophy and di-lation, with tricuspid regurgitation and de-creased ventricular function, while no spe-cific acquired cardiac dysfunction occurs indonors either in utero or after birth.29,31,32,66,67
Volume overloading and systemic hyper-tension in the recipient cause myocardialhypertrophy.29 This hypertrophic cardiomy-opathy can cause subvalvular stenosis re-sulting in right ventricular outflow tract ob-struction necessitating valvotomy in infancyin some cases.31,32 Though biventricular hy-pertrophy is frequent in recipients, an ac-quired right outflow tract anomaly has beendescribed in absence of systemic hyperten-sion.68 Cardiac hypertrophy is associatedwith subsequent cerebral palsy, althoughthis may simply be a function of diseaseseverity.60 Although 45% to 50% of recipi-ents exhibit abnormal cardiac function in
the neonatal period; most of these changesare reversible, however, 5% to 10% ofthe recipients have long-term cardiac prob-lems.31,32,43,66,67
Interestingly, follow up studies in off-spring of TTTS pregnancies show abnormalvascular function including reduced arterialdistensibility in donors versus recipients,possibly due to vascular programming inutero, with implications for cardiovasculardisease in adult life as proposed by Barker.69
Of note, these changes in vascular functionare absent in double survivors after laser, inwhich ablation of anastomoses curtailed fur-ther intertwin transfusion in utero.70
OTHER COMPICATIONSAcute neonatal renal failure occurs morecommonly in TTTS. A prospective cohortstudy of 17 pregnancies described a 48% in-cidence of renal failure in survivors (donor >recipient) compared with 14% in gestationalage-matched control twins.35 However, thisrenal failure is often transient, long term re-nal sequelae occurring in only 3% of survi-vors.35,43,63 Abnormal perfusion in othervascular beds may also result in fetal/neonatalcomplications. Reduced splanchnic perfu-sion can lead to congenital intestinal per-foration from ischemic necrosis.35,43,63
Spontaneous lower extremity ischemia re-sulting in amputations have also been de-scribed.36,43,57
ManagementThe range of therapeutic options includesexpectant management, serial amnioreduc-tion, septostomy, laser photocoagulation ofplacental shunts, and selective feticide. Be-cause of the high untreated perinatal mortal-ity and morbidity, expectant managementwill only be appropriate in a few mild cases.
MEDICAL THERAPYSome empiric medical treatments have beentried. However, none to date have proven tobe of benefit. With a view to improving car-diac function in the recipient, maternal di-
TwinTwin Transfusion 189
goxin therapy has been used with anecdotalsuccess.71 However, the ability of digoxin tocross the placenta and reach the recipient intherapeutic concentrations, especially in thepresence of hydrops, is questionable. Indo-methacin to control polyhydramnios in therecipient is contraindicated in view of its ex-acerbating effect on the already compro-mised donors renal function.
AMNIOREDUCTIONSerial amnioreduction to normalize amni-otic fluid volume is the earliest and arguablythe simplest and most accessible of the vari-ous treatments advocated in TTTS.37 Themost obvious mechanism by which amnio-reduction works is decreased fluid volumereducing the risk of preterm labor andPPROM.72 Patients with polyhydramnioshave raised amniotic pressure and its reduc-tion is associated with improvement in fetalstatus.27 Polyhydramnios is associated withimpaired uteroplacental perfusion as sug-gested by an inverse correlation between thedegree of hydramnios and impairment in fe-tal blood gases.73 Amnioreduction leads to a74% increase in uterine arterial flow, whichsuggests a further mechanism for the benefi-cial effects of amnioreduction.26 PPROM inTTTS may paradoxically improve outcomeby a similar mechanism.
Amniocentesis is indicated when amni-otic fluid index (AFI) is >40 cm or the deep-est vertical pool >12 cm, the threshold forincreased amniotic pressure. Each liter offluid reduces AFI by about 10 cm. Previ-ously, the goal was to lower the AFI to
reported benefit was a decrease in need forrepeat procedures with septostomy (40%versus 70% with amnioreduction). In termsof technique, Nd:YAG laser can be used asan alternative to needling to create the defectin the intertwin membrane, though withoutany significant advantages.75 The procedurehas at least a theoretical risk of intertwincord entanglement through extension of thedefect in the dividing membrane, though thehole created is usually small (microseptos-tomy).
Despite its ameliorative effects, it is againdifficult to see how septostomy addressesthe underlying transfusional basis of the dis-ease. In this light, computer modeling hasshown that merging of the two amnioticcompartments to allow swallowing of the re-distributed fluid by the donor has minimaleffect on donor blood volume or growth.80,81
LASER ABLATIONLaser ablation is the only treatment that ad-dresses the primary basis of the disease; ces-sation of intertwin transfusion. Laser abla-tion entails photocoagulation of anastomoticvessels between the two chorionic circula-tions under direct vision. Typically, an en-doscope is introduced transabdominally intothe uterine cavity under ultrasound guidanceand Nd:YAG laser applied via a 400600m optic fiber introduced thorough the sidechannel.82,83
Non-Selective Laser AblationIn this initial technique, all vessels ap-proaching or crossing the membrane be-tween the twins were ablated.84 However,this approach met with limited success.Ville et al carried out laser ablation of pla-cental anastomoses in a series of 132 pa-tients with severe TTTS at a median gesta-tional age of 21 weeks. Overall fetal survivalwas 55%, and the number of pregnancieswith at least 1 survivor was 73%.58 De Liareported a 69% overall survival and 82% ofpregnancies had at least 1 survivor in a seriesof 74 patients, though 7 patients were ex-cluded from analysis due to pre- or intraop-
erative complications.57 A meta-analysis ofTTTS presenting before 28 weeks con-cluded that outcomes from non-selective la-ser ablation were similar to serial amniore-duction with a 58% overall survival and atleast one survivor in 74 versus 70% of preg-nancies.1
A likely explanation for the lack of im-proved survival with non-selective laser ab-lation is that since the intertwin membranebears little relationship to the vascular equa-tor between the two fetoplacental circula-tions, a number of non-anastomotic vesselsare also obliterated; devitalizing some nor-mal cotyledons.72,85 The excessive placen-tal insult is substantiated by findings of fullthickness placental necrosis postpartum.82
Such an insult is more detrimental to the do-nor with a lesser a priori placental share.This explains the high procedure related fe-tal loss rate, which was as high as 42% in thefirst series though subsequently decreased to15-20%.58,84 In keeping with this hypoth-esis, two thirds of donors die if AEDF is pres-ent prior to laser. Other complications in-clude PPROM, chorioamnionitis, pretermlabor, and continued or even reversedTTTS.86 Rare findings including aplasia cu-tis, limb necrosis, amniotic bands, and mi-crophthalmia, have been described, but theircausal relationship to the procedure ratherthan TTTS has not been established.57,87
Anecdotal reports of maternal complica-tions such as pulmonary edema, adult respi-ratory distress syndrome and maternal deathare of concern, although the contribution oflaser as opposed to the concomitant amnio-reduction is unclear.
Selective Laser AblationTo minimize the high procedure related lossrate of non-selective ablation, severalgroups developed selective photocoagula-tion targeting only those AVAs involved inthe donor-to-recipient transfusion.11,39,40,59,88
Vessels near the intertwin membrane arecarefully examined endoscopically to iden-tify AVAs. All AVAs including reverseones from the recipient to donor are photo-
TwinTwin Transfusion 191
coagulated to prevent any reversal of thetransfusional phenotype.89 The anastomoticconfiguration can be variable making cor-rect identification challenging and in thislight, endoscopically identified AVAs havenot been validated against gold standard pla-cental injection studies. Visual examinationunder optimal ex vivo conditions identifiedonly two-thirds of AVAs demonstrated byplacental injection.21a AVAs can be identi-fied in vivo using color Doppler and 3D ul-trasound which may facilitate planning ofselective laser ablation and result in shorterprocedure times, although the sensitivity ofthis technique to date remains < 50% (un-published observations).90,91
There are a number of technical chal-lenges with both types of laser treatment.Access to an anterior placenta is a particularproblem. A lateral entry, use of flexiblecurved or sidefiring scope and even a mini-laparotomy to insert the cannula directlyinto the uterus have been used in attempts toovercome this problem.58,87,88 Access mayalso be facilitated by adequate maternal an-esthesia, such as under epidural or general,although not all groups find this necessary.Prior septostomy may occasionally renderaccess to the chorionic plate problematic dueto chorioamniotic separation, while intra-amniotic bleeding secondary to vessel dis-ruption may necessitate amnioexchange torestore visualization.
Treatment is followed by improvement infetal hemodynamics including restoration ofnormal ductus venosus flow in the recipientand normal umbilical artery flow in the do-nor.86 However, the donor may show signsof a transient hydrops, which may be the re-sult of normalization of a previously hypo-dynamic circulation.86 Around 13% of pa-tients require a repeat procedure.40,58 An an-ecdotal report of a superselective laserablation procedure describes identificationand ablation of a single donor-to-recipientAVA.92 However, when selective ablationof anastomoses from the donor to the recipi-ent is undertaken, the possibility of reversal
of TTTS along residual anastomoses di-rected from recipient to donor needs to bekept in mind.89
Using the selective laser, Quintero et alreported survival of at least one fetus in 83%of patients versus 61% in a non-selective la-ser group and 67% in a serial amniocentesisgroup managed in the same center.54,59
Similarly, Hecher et al showed an improvedoverall survival of 68% with selective laser(versus 61% in a non-selective laser groupand 51% in non-contemporaneous amnio-drainange control group from another cen-ter) with survival of at least one fetus in 81%(versus 79% and 60%, respectively).39,40
However, a double survival of only 54%, in-dicates that even with the best treatment op-tion available, almost half of affected preg-nancies still lose one or more fetuses.40
In terms of neurologic sequelae, Quinteroet al suggested that selective laser led to adecrease in the incidence of neurologic mor-bidity (4% versus 24% in the non-selectivegroup), though without differentiating be-tween cranial ultrasound abnormalities andneurologic handicap.54 Hecher et al alsosuggested a lower incidence of abnormalcranial ultrasound findings with selective la-ser treatment (6% versus 18% in an amnio-reduction group managed elsewhere).39
However, a formal neurodevelopmental fol-low up study of 89 TTTS survivors at 14 to33 months by the same group subsequentlyshowed a 22% incidence of neurologic se-quelae in the selective laser treated group in-cluding an 11% incidence of cerebralpalsy.56 The incidence was similar in donorsand recipients. However, it was increased insingle survivors after an intrauterine death(27% versus 8% in double survivors), inwhich case it was more likely to be in recipi-ents (23% versus 14% in donors) as com-pared with double survivors (3% in recipi-ents versus 13% donors).56 In the absence offormal long term neurologic follow up, Villeet al also reported a seemingly low neuro-logic handicap rate of 4% with non-selectivelaser.58 However, detailed neurodevelop-mental follow up by the same group at 6
192 Jain and Fisk
months to 3 years showed a 9% incidence ofcerebral palsy.93 Considering all the data, itappears that the incidence of cerebral palsywith non-selective and selective laser iscomparable to the overall incidence of cere-bral palsy in TTTS (8%) and argues againstan obvious improvement in neurologic out-come with laser therapy. However, Sutcliffeet al found no cases of cerebral palsy insingle survivors following non-selective la-ser treatment, suggesting that non-selectivelaser may result in single intrauterine death,the resultant functionally dichorionic pla-centae protect against agonal transfusionalsequelae.93 An alternative explanation couldbe that this treatment modality improvesoverall survival merely by salvaging fetusesthat have already suffered a neurologic in-sult.
SELECTIVE FETICIDEIn contrast to other treatments which attemptto salvage both fetuses, with selective feti-cide one fetus is killed by cord litigation toimprove the chance of survival in the other.Due to its inherent procedure related mortal-ity of at least 50%, feticide was initially re-served for cases where other treatmentsfailed, and in particular where one fetus wasdeemed preterminal. More recently it hasbeen offered to patients with severe TTTS(Stage III or IV) as an alternative to selectivelaser ablation with the surmise that a betterintact prognosis for one twin may be prefer-able to a guarded prognosis for both. Afterthe decision has been made to proceed, thequestion that arises is which fetus to termi-nate. Initially, donors were selected basedon the assumption that a donor with AEDFhas defective placentation impairing its sub-sequent intrauterine longevity. In addition,the recipient was felt less likely to exsangui-nate into the donor against the net AVAtransfusional direction. Both assumptionshave been proven to be incorrect. Post-procedure survival and growth velocities ofspared recipient and donor co-twins havebeen similar, making the recipient and thedonor equally appropriate choices for cord
ligation.94 In addition, preprocedural Dopp-ler abnormalities normalize postprocedurein surviving donors.94 Current evidence sug-gests that the recipient may be a better can-didate for termination for several reasons.Technically, targeting the cord in the recipi-ent sac with polyhydramnios is easier. Thecord can be occluded well away from theuterine wall decreasing the risk of maternalinjury. In addition, recipients are more likelyto develop hydrops and cardiac dysfunction,and may have a higher incidence of neuro-logic sequelae.31,38,60,61,6668 Nonetheless,there remain indications for selective feti-cide of the donor eg, severe brain lesions orcardiac defects in donor or increased cordthickness in the recipient (>26 weeks or withhydrops) rendering cord occlusion problem-atic. One disadvantage with selecting thedonor is that amnioinfusion is often requiredto access the cord.94
Any technique used must ensure that allvessels in the umbilical cord are occluded,failure of which can lead to acute intertwintransfusion. Ultrasound-guided sclerosantinjection techniques95,96 occlude only onevessel which explains the failure rate of 67%reported using alcohol or enbucrilate.97 La-ser coagulation of the cord is usually not fea-sible after 18 to 20 weeks because of ahigher failure rate with increasing vessel di-ameter.98 A fetoscopic approach has beenused to place a suture knot around the cordwith success rates as high as 84%.99101
Overall survival (of the surviving twin) withfetoscopic suture ligation of the cord is 63%to 71% with an associated risk of pretermrupture of membranes as high as 30% to40%.99,101 Suture ligation of the cord canalso be done entirely under ultrasound guid-ance.102
The preferred method for selective feticidein MC twins is now the simpler ultrasound-guided approach with bipolar diathermy.94
A single 3.3 mm port is introduced into theamniotic cavity under local anesthesia (Fig.4) and 3 mm bipolar diathermy forceps ad-vanced under ultrasound guidance to graspa free loop of cord away from the both the
TwinTwin Transfusion 193
fetus and the uterine wall. Serial applica-tions of coagulation lasting 60 seconds areused with incremental power as needed (20to 50 W) until the bubbling stops. Cessationof blood flow is confirmed by color Doppler.Advantages include use of a single port, ahigh success rate in achieving cord occlu-sion, a shorter procedure duration, a 76% to93% survival of the remaining twin, and alower albeit substantial (12% to 20%) inci-dence of PPROM.94,103,104 An importantaspect of this treatment is the varying legalstatus of termination of pregnancy after vi-ability. This option may be feasible after 24weeks in jurisdictions such as the UnitedKingdom, France and Israel but is notwidely available in other countries includingmost of the United States.
A novel recently developed interstitial la-ser procedure is useful for selective termina-tion in the early mid trimester (
ents to countenance termination of a struc-turally normal fetus, along with the naturaltendency of clinicians to delay such a proce-dure until it becomes absolutely necessary,which obviously can result in an unexpectedfetal loss.
MANAGEMENT OF SINGLEINTRAUTERINE DEATHIn the event of death of one twin, the TTTSphenotype may resolve, but close monitor-ing of the surviving co-twin is essential todetect acute transfusional sequelae. Fetalblood sampling has been carried out fol-lowed by intrauterine blood transfusion tocorrect anemia in an attempt to improve sur-vival and perhaps reduce neurologic diseasein survivors.46 However, emergency trans-fusion seems too late to prevent neurologicinjury and may lead to increased survival ofbrain damaged fetuses. Similarly, immedi-ate delivery does not improve outcome forthe surviving fetus, presumably because theinsult has already occurred.45 In contrastconservative management with ultrasonog-raphy and magnetic resonance imaging(MRI) allows detection of significant neuro-logic injury. Abnormal cranial ultrasoundfindings are reported in 50% of survi-vors.36 When imaging suggests a major riskof neurologic sequelae, termination of preg-nancy can be considered within the localgestational and legal constraints. Clearly,prevention of the first intrauterine death andits sequelae is the preferable goal; thus care-ful monitoring of TTTS pregnancies is cru-cial to facilitating a diagnosis of impendingfetal death rather than fetal death itself.When intrauterine death is imminent, deliv-ery, laser or at least occlusive feticide mayprevent these devastating complications.Finally, despite anecdotal reports of sub-clinical coagulopathy in the mother after in-trauterine death of one twin, there is no evi-dence to implicate disseminated intravascu-lar coagulation as a sequelae of single MCintrauterine death.45
DELIVERYAfter viability, delivery becomes an option,keeping in mind the poorer fetal outcome atgestations
is increasingly used to guide management,with simpler relatively safe but possibly lesseffective procedures like amnioreductionand septostomy preferred for good progno-sis cases. Technically-challenging proce-dures like cord occlusion and endoscopic la-ser ablation, which are seemingly more ef-fective but with a higher intrinsic risk offetal loss, being employed in poor prognosiscases. There are now strong arguments for astage-based approach to therapy. Quinteroet al in a multicenter cohort comparison ofsurvival by stage recently reported resultswhich showed that laser had a higher perina-tal death rate compared with serial amniore-duction (29% versus 13%, OR 2.7 (95% CI1.1-7.0), P = 0.02) in early disease with fluidbalance changes only (stage I and II) (Fig.5). In contrast, in advanced disease with car-diovascular manifestations (stage III andIV), laser had a lower perinatal death rate(45% versus 65%, OR 0.4 (95% CI 0.20.9),P < 0.02). The double survival rate in stage Iand II was similarly higher for amnioreduc-tion (79% versus 55% for laser, OR 3.1
(95% CI 1.28.3), P = 0.02). Thus, the num-ber needed to treat (NNT) for amnioreduc-tion versus laser in early stage disease indi-cated an extra double survival for every fouror five cases treated by amnioreductioncompared with laser. Since some cases withAR will progress, if this analysis had beendone for worst rather than initial stage, thesurvival advantage in early disease may beeven greater in favor of amnioreduction.Analysis of another useful parameter to as-sess pregnancy outcome, any (or at leastone) survival rate, was higher for laser instage III and IV (82% versus 45% for am-nioreduction, OR 2.8 (95% CI 1.716.7), P< 0.01). Thus, in advanced disease, the NNTfor laser versus amnioreduction indicatedthat every third patient treated with laser re-sulted in an extra pregnancy with at least 1survivor. In conclusion, serial amnioreduc-tion and/or septostomy is associated withbetter outcomes in stage I or II disease, whileselective laser ablation is associated withbetter outcomes in advanced disease (stageIII/IV).
FIGURE 5. Categorical reanalysis of survival data from twin-twin trans-fusion syndrome (TTTS)-affected pregnancies treated with amnioreductionor selective laser (Quintero et al, Am J Obstet Gynecol 2003;188:13331340). Panel A: Perinatal (overall), double (both twins) and any (at least one)survival rates in mild (combined stage I and II) TTTS. Panel B: Survivalrates in severe (combined stage III and IV) TTTS. *versus amnioreduction,P < 0.05.
196 Jain and Fisk
Our suggested sub-categorization ofQuintero stage, in which the presence or ab-sence of an antenatally-detected AAA is de-noted a and b respectively, not only al-lows identification of good from bad prog-nosis cases within each stage, but also anAAA-positive subgroup within Stage III(IIIa) which is associated with better perina-tal and double survival than AAA-negativeStage I and II (Ib and IIb) cases.49 Incorpo-ration of AAA into a modified TTTS stagingsystem should improve prediction of perina-tal survival, and may facilitate treatment se-lection to optimize outcome. Stages Ia, IIaand IIIa form a group with good survivalprognosis, which can be managed conserva-tively or with temporizing measures such asamnioreduction and/or septostomy, andthen delivered electively by 32 to 34 weeks.Stages Ib and IIb comprise a group with in-termediate survival prognosis. While am-nioreduction is associated with better peri-natal survival than laser ablation for StageIII,54 some of this group nevertheless prog-ress to more advanced stage disease, even-tually requiring definitive treatment. StagesIIIb and IV form the group with the poorestsurvival, in which more invasive albeit de-finitive treatment such as selective laser orcord occlusion appear indicated. Selectivelaser ablation of anastomotic vessels hasbeen shown to result in higher perinatal,double and any survival rates than amnio-centesis procedures for stage IV disease,54
while cord occlusion in Stage III/IV diseaseis associated with empirically higher sur-vival than amnioreduction.94
Notwithstanding this, there are some ar-guments against a stage based approach totreatment. Firstly, little information is avail-able on neurologic sequelae by stage, and fu-ture studies will now be needed to stratify bymodified stage. Next a proportion of pa-tients with early stage disease will progressto require more definitive treatment, andmembranous detachment after septostomyor intra-amniotic bleeding after amniore-duction may render laser technically diffi-cult, reducing the chances of success. Fi-
nally, in Stage IV disease, the rare presenceof an AAA seems to worsen prognosis, pre-sumably by allowing acute transfusion withits sequalae when one twin dies in utero.48,49
ConclusionTTTS is a common disease process affectingmonochorionic diamniotic pregnancies.Though the pathophysiology is poorly un-derstood, interplacental anastomoses andunbalanced intertwin transfusion form theetiologic basis. Several therapeutic optionsare available including amnioreduction,septostomy, laser ablation of vascular anas-tomoses, and selective feticide. With thesemodern treatment modalities, overall peri-natal survival rates have improved from20% to around 60% to 70%. However, themajority of affected pregnancies will stilllose at least one baby, with significant longterm neurologic morbidity in about 10% ofthe survivors. Thus, outcomes, though sub-stantially improved by intervention, remainsuboptimal, partly due to poor understand-ing of the underlying pathophysiology andpartly because of poor case selection for in-tervention. Current evidence supports astage-based approach to treatment, with afurther survival advantage conferred by thepresence of an AAA. Conservative treat-ment such as amnioreduction and septos-tomy are favored for early stage disease. Inadvanced disease, with a
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