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SMFM Clinical Guideline www.AJOG.org

Twin-twin transfusion syndrome
Society for Maternal-Fetal Medicine (SMFM), with the assistance of Lynn L. Simpson, BSc, MSc, MD
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Question 1. How is the diagnosis oftwin-twin transfusion syndromemade and how is it staged?(Levels II and III)Twin-twin transfusion syndrome (TTTS)is diagnosed prenatally by ultrasound.The diagnosis requires 2 criteria: (1) thepresence of a monochorionic diamniotic(MCDA) pregnancy; and (2) the pres-ence of oligohydramnios (defined as amaximal vertical pocket [MVP] of �2cm) in one sac, and of polyhydramnios(a MVP of �8 cm) in the other sac(Figure 1).1 MVP of 2 cm and 8 cm rep-esent the 5th and 95th percentiles formniotic fluid measurements, respec-ively, and the presence of both is used toefine stage I TTTS.2 If there is a subjec-

tive difference in amniotic fluid in the 2sacs that fails to meet these criteria, pro-gression to TTTS occurs in �15% ofcases.3 Although growth discordanceusually defined as �20%) and intra-terine growth restriction (IUGR) (esti-ated fetal weight �10% for gestational

ge) often complicate TTTS, growth dis-ordance itself or IUGR itself are not di-gnostic criteria.4 The differential diag-osis may include selective IUGR, orossibly an anomaly in 1 twin causingmniotic fluid abnormality.5 Twin ane-ia-polycythemia sequence (TAPS) has

een recently described in MCDA gesta-ions, and is defined as the presence ofnemia in the donor and polycythemian the recipient, diagnosed antenatally by

iddle cerebral artery (MCA)–peak sys-olic velocity (PSV) �1.5 multiples of

From the Society for Maternal-Fetal MedicinePublications Committee, Washington, DC; andthe Department of Obstetrics & Gynecology,Columbia University Medical Center, NewYork, NY (Dr Simpson).

Received Sept. 23, 2012; revised Oct. 3, 2012;accepted Oct. 19, 2012.

The authors report no conflict of interest.

Reprints are not available from the authors.

0002-9378/free© 2013 Mosby, Inc. All rights reserved.
http://dx.doi.org/10.1016/j.ajog.2012.10.880
edian in the donor and MCA PSV1.0 multiples of median in the recipi-

nt, in the absence of oligohydramnios-olyhydramnios.6 Further studies are re-

quired to determine the natural history

OBJECTIVE: We sought to review the nattreatment options for twin-twin transfusionMETHODS: A systematic review was perfEMBASE, and Cochrane Library. The searchlished from 1966 through July 2012. Priresearch, in particular randomized controlletaries also were consulted. Abstracts of reconferences were not considered adequareports and guidelines published by organInstitutes of Health, Agency for Health Resetricians and Gynecologists, and Society forand additional studies were located by reConsistent with US Preventive Task Force gubased on the highest level of evidence, andRESULTS AND RECOMMENDATIONS: TTT8-10% of twin pregnancies with monochdiagnosis of TTTS requires 2 criteria: (1) thpresence of oligohydramnios (defined as aand of polyhydramnios (a maximal vertical pstaging system appears to be a useful tstandardized fashion. Serial sonographic evMCDA placentation, usually beginning at arweeks until delivery. Screening for congenirionic twins, in particular those complicatprovided to patients with pregnancies compdisease, as well as management options anof stage I TTTS is that more than three-fouinvasive intervention, with perinatal survivastage I TTTS may often be managed expecta�III) TTTS is bleak, with a reported perinapresents �26 weeks. Fetoscopic laser pconsidered by most experts to be the best ain continuing pregnancies at �26 weeks,survival benefit, and the long-term neurolodifferent than in nonlaser-treated controls.perinatal mortality rate of 30-50%, and a 5cap. Steroids for fetal maturation shouldparticularly in pregnancies complicated by sinterventions.

Key words: amnioreduction, fetoscopy, lastwin-twin transfusion syndrome

and possible management of TAPS.

JANUARY 2013 A

TTTS can occur in a MCDA twin pair intriplet or higher-order pregnancies.

The most commonly used TTTS stag-ing system was developed by Quintero etal2 in 1999, and is based on sonographic

l history, pathophysiology, diagnosis, anddrome (TTTS).ed using MEDLINE database, PubMed,restricted to English-language articles pub-

y was given to articles reporting originalials, although review articles and commen-rch presented at symposia and scientificfor inclusion in this document. Evidencetions or institutions such as the Nationalh and Quality, American College of Obste-ternal-Fetal Medicine were also reviewed,wing bibliographies of identified articles.lines, references were evaluated for qualitycommendations were graded accordingly.s a serious condition that can complicatenic diamniotic (MCDA) placentation. Theesence of a MCDA pregnancy; and (2) theimal vertical pocket of �2 cm) in one sac,et of �8 cm) in the other sac. The Quinterofor describing the severity of TTTS in ation should be considered for all twins withd 16 weeks and continuing about every 2eart disease is warranted in all monocho-

by TTTS. Extensive counseling should beted by TTTS including natural history of theheir risks and benefits. The natural historyof cases remain stable or regress without

about 86%. Therefore, many patients with. The natural history of advanced (eg, stageloss rate of 70-100%, particularly when itcoagulation of placental anastomoses isable approach for stages II, III, and IV TTTSthe metaanalysis data show no significantoutcomes in the Eurofetus trial were notn laser-treated TTTS is associated with a% chance of long-term neurologic handi-considered at 24 0/7 to 33 6/7 weeks,e �III TTTS, and those undergoing invasive

hotocoagulation, monochorionic twins,

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system includes 5 stages, ranging frommild disease with isolated discordantamniotic fluid volume to severe diseasewith demise of one or both twins (Table 1and Figures 2 and 3). This system hassome prognostic significance and pro-vides a method to compare outcomedata using different therapeutic inter-ventions.2 Although the stages do notorrelate perfectly with perinatal sur-ival,7 it is relatively straightforward to

apply, may improve communication be-tween patients and providers, and iden-tifies the subset of cases most likely tobenefit from treatment.8,9

Since the development of the Quin-tero staging system, much has been

FIGURE 1Polyhydramnios-oligohydramnios s

Monochorionic diamniotic twins with twin-twin trin recipient’s sac (twin A) while donor (twin B)oligohydramnios.Reproduced with permission from Simpson.1

SMFM. Twin-twin transfusion syndrome. Am J Obstet Gyne

TABLE 1Staging of twin-twin transfusion sy

Stage Ultrasound parameter

I MVP of amniotic fluid

...................................................................................................................

II Fetal bladder

...................................................................................................................

III Umbilical artery, ductus venosus, andumbilical vein Doppler waveforms

...................................................................................................................

IV Fetal hydrops...................................................................................................................

V Absent fetal cardiac activity...................................................................................................................

MVP, maximal vertical pocket.

SMFM. Twin-twin transfusion syndrome. Am J Obstet Gynec

4 American Journal of Obstetrics & Gynecology JA

learned about the changes in fetal cardio-vascular physiology that accompany dis-ease progression (discussed below).Myocardial performance abnormalitieshave been described, particularly in re-cipient twins, including those with onlystage I or II TTTS.10 Several groups ofnvestigators have attempted to use as-essment of fetal cardiac function to ei-her modify the Quintero TTTS stage11

or develop a new scoring system.12 Whilehis approach has some benefits, the

odels have not yet been prospectivelyalidated. As a result, a recent expertanel concluded that there were insuffi-ient data to recommend modifying theuintero staging system or adopting a

uence

fusion syndrome demonstrating polyhydramnioss stuck to anterior uterine wall due to marked

013.

rome2

ategorical criteria

VP �2 cm in donor sac; MVP �8 cm incipient sac

..................................................................................................................

onvisualization of fetal bladder in donor twinver 60 min of observation (Figure 2)..................................................................................................................

bsent or reversed umbilical artery diastolicow, reversed ductus venosus a-wave flow,ulsatile umbilical vein flow (Figure 3)..................................................................................................................

ydrops in one or both twins..................................................................................................................

etal demise in one or both twins..................................................................................................................

ol 2013.

NUARY 2013

ew system.8 Thus, despite debate overhe merits of the Quintero system, at thisime it appears to be a useful tool for theiagnosis of TTTS, as well as for describ-

ng its severity, in a standardized fashion.

Question 2. How often does TTTScomplicate monochorionic twinsand what is its natural history?(Levels II and III)Approximately one-third of twins aremonozygotic (MZ), and three-fourths ofMZ twins are MCDA. In general, only

FIGURE 2Stage II twin-twin transfusionsyndrome

Nonvisualization of fetal bladder (arrow) betweenumbilical arteries in donor twin.Reproduced with permission from Simpson.1

SMFM. Twin-twin transfusion syndrome. Am J ObstetGynecol 2013.

FIGURE 3Stage III twin-twin transfusionsyndrome

Absent end-diastolic flow (arrows) in umbilicalartery of donor twin.Reproduced with permission from Simpson.1

SMFM. Twin-twin transfusion syndrome. Am J ObstetGynecol 2013.

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www.AJOG.org SMFM Clinical Guideline

twin gestations with MCDA placenta-tion are at significant risk for TTTS,which complicates about 8-10% ofMCDA pregnancies.13,14 TTTS is veryuncommon in MZ twins with dichori-onic or monoamniotic placentation.15

Although most twins conceived with invitro fertilization (IVF) are dichorionic,it is important to remember that there isa 2- to 12-fold increase in MZ twinningin embryos conceived with IVF, andTTTS can therefore occur for IVFMCDA pregnancies.16,17 In current

ractice, the prevalence of TTTS is ap-roximately 1-3 per 10,000 births.18

The presentation of TTTS is highlyvariable. Because pregnancies with TTTSoften receive care at referral centers, dataabout the stage of TTTS at initial presen-tation (ie, to nonreferral centers) arelacking in the literature. Fetal therapycenters report that about 11-15% of theircases at referral were Quintero stage I(probably underestimated as some refer-ral centers did not report stage I TTTScases), 20-40% were stage II, 38-60%were stage III, 6-7% were stage IV, and2% were stage V.5,9 Although TTTS maydevelop at any time in gestation, the ma-jority of cases are diagnosed in the sec-ond trimester. Stage I may progress to anonvisualized fetal bladder in the donor(stage II) (Figure 2), and absent or re-versed end-diastolic flow in the umbili-cal artery of donor or recipient twinsmay subsequently develop (stage III)(Figure 3), followed by hydrops (stageIV). However, TTTS often does notprogress in a predictable manner. Natu-ral history data by stage are limited, es-pecially for stages II-V, as staging wasinitially proposed in 1999.2 This is be-cause most natural history data werepublished before 1999, and therefore wasnot stratified by stage (Table 2).19-21

Over three fourths of stage I TTTS casesremain stable or regress without invasiveinterventions (Table 2).19-21 The natural

istory of advanced (eg, stage �III)TTS is bleak, with a reported perinatal

oss rate of 70-100%, particularly when itresents �26 weeks.22,23 It is estimatedhat TTTS accounts for up to 17% of theotal perinatal mortality in twins, and forbout half of all perinatal deaths in
CDA twins.13,24 Without treatment, c
the loss of at least 1 fetus is common,with demise of the remaining twin oc-curring in about 10% of cases of twin de-mise, and neurologic handicap affecting10-30% of cotwin remaining survi-vors.25-27 Overall, single twin survivalrates in TTTS vary widely between 15-70%, depending on the gestational age atdiagnosis and severity of disease.22,26

The lack of a predictable natural history,and therefore the uncertain prognosisfor TTTS, pose a significant challenge tothe clinician caring for MCDA twins.

Question 3. What is the underlyingpathophysiology of TTTS?(Levels II and III)The primary etiologic problem underly-ing TTTS is thought to lie within the ar-chitecture of the placenta, as intertwinvascular connections within the placentaare critical for the development of TTTS.Virtually all MCDA placentas have anas-tomoses that link the circulations of thetwins, yet not all MCDA twins developTTTS. There are 3 main types of anasto-moses in monochorionic placentas:venovenous (VV), arterioarterial (AA),and arteriovenous (AV). AV anastomo-ses are found in 90-95% of MCDA pla-centas, AA in 85-90%, and VV in 15-20%.28,29 Both AA and VV anastomosesre direct superficial connections on theurface of the placenta with the potentialor bidirectional flow (Figure 4). In AVnastomoses, while the vessels them-elves are on the surface of the placenta,he actual anastomotic connections oc-ur in a cotyledon, deep within the pla-enta (Figure 4). AV anastomoses can re-ult in unidirectional flow from one twino the other, and if uncompensated, mayead to an imbalance of volume betweenhe twins. Unlike AA and VV, which areirect vessel-to-vessel connections, AV

TABLE 2Natural history of stage I twin-twin

StageIncidence of progressionto higher stage

I 6/39 (15%)...................................................................................................................

SMFM. Twin-twin transfusion syndrome. Am J Obstet G

onnections are linked through large

JANUARY 2013 A

apillary beds deep within the cotyledon.V anastomoses are usually multiplend overall balanced in both directionso that TTTS does not occur. While theumber of AV anastomoses from donor

o recipient may be important, their sizes well as placental resistance likely influ-nces the volume of intertwin transfu-ion that occurs.30 Placentas in twins af-

fected with TTTS are reportedly morelikely to have VV, but less likely to haveAA anastomoses.28 It is thought thathese bidirectional anastomoses mayompensate for the unidirectional flowhrough AV connections, thereby pre-enting the development of TTTS or de-reasing its severity when it does occur.31

Mortality is highest in the absence of AAand lowest when these anastomoses arepresent (42% vs 15%).29 However, thepresence of AA is not completely protec-tive, as about 25-30% of TTTS cases mayalso have these anastomoses.32 The im-

alance of blood flow through the pla-ental anastomoses leads to volume de-letion in the donor twin, with oliguria

ansfusion syndrome19-21

dence of resolution,ression to lowere, or stability Overall survival

9 (85%) 102/118 (86%)..................................................................................................................

l 2013.

FIGURE 4Selected anastomoses inmonochorionic placentas

Courtesy of Vickie Feldstein, University of California, SanFrancisco.

a-a, arterioarterial anastomosis; a-v, arteriovenous anastomosis;-a, venous-arterial anastomosis.

MFM. Twin-twin transfusion syndrome. Am J Obstetynecol 2013.

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and oligohydramnios, and to volumeoverload in the recipient twin, with poly-uria and polyhydramnios.

There also appear to be additional fac-tors beyond placental morphology, such ascomplex interactions of the renin-angio-tensin system in the twins,33-35 involved inthe development of this disorder.

Question 4. How should monochorionictwin pregnancies be monitored for thedevelopment of TTTS? (Levels II and III)All women with a twin pregnancy shouldbe offered an ultrasound examination at10-13 weeks of gestation to assess viabil-ity, chorionicity, crown-rump length,and nuchal translucency. TTTS usuallypresents in the second trimester, and is adynamic condition that can remain sta-ble throughout gestation, occasionally

FIGURE 5Algorithm for screening for TTTS

MCDA p

First tr

- Confirm modiamnio�c p

- NT screenin

~ 1

Start ultrasound surveillance with MVfetus, every 2 weeks, until delivery

MVP >2cm and <8

Con�nue ultrasound surveillance every 2 weeks

Yes

MCDA, monochorionic diamniotic; MVP, maximum vertical pocke


regress spontaneously, progress slowly


over a number of weeks, or developquickly within a period of days withrapid deterioration in the well-being ofthe twins. There have been no random-ized trials of the optimal frequency of ul-trasound surveillance of MCDA preg-nancies to detect TTTS. Although twinpregnancies are often followed up withsonography every 4 weeks, sonographyas often as every 2 weeks has been pro-posed for monitoring of MCDA twinsfor the development of TTTS.36-38 This isn part because, while stage I TTTS haseen observed to remain stable or resolve

n most cases, when progression does oc-ur it can happen quickly.39 However,

studies that have focused on progression ofearly-stage TTTS may not be applicable tothe question of disease development in ap-

ancy

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n each sac, and fetal bladder in each

in each sac

MVP <2cm in 1 sac and MVP >8 cm inother sac: Diagnosis = TTTS

See Figure 10

No

, nuchal translucency; TTTS, twin-twin transfusion syndrome.

013.

parently unaffected pregnancies.

NUARY 2013

Given the risk of progression fromstage I or II to more advanced stages, andthat TTTS usually presents in the secondtrimester, serial sonographic evaluationsabout every 2 weeks, beginning usuallyaround 16 weeks of gestation, until de-livery, should be considered for all twinswith MCDA placentation, until more dataare available allowing better risk stratifica-tion37,38 (Figure 5). Sonographic surveil-ance less often than every 2 weeks has beenssociated with a higher incidences of late-tage diagnosis of TTTS.40 This under-cores the importance of establishinghorionicity in twin pregnancies as earlys possible.41 These serial sonographicvaluations to screen for TTTS shouldnclude at least MVP of each sac, and theresence of the bladder in each fetus.mbilical artery Doppler flow assess-ent, especially if there is discordance in

uid or growth, is not unreasonable, butata on the utility of this added screeningarameter are limited. There is no evi-ence that monitoring for TAPS withCA PSV Doppler at any time, includ-

ng �26 weeks, improves outcomes, sohat this additional screening cannot beecommended at this time.6

In addition to monitoring MCDApregnancies for development of amni-otic fluid abnormalities, there are severalsecond- and even first-trimester sono-graphic findings that have been associatedwith TTTS. These findings are listed in Ta-ble 3.28,42-49 Before 14 weeks, MCDA twinsan be evaluated with nuchal translucencynd crown-lump length. Nuchal translu-ency abnormalities and crown-lumpength discrepancy have been associatedith an increased risk of TTTS.28,29,38 If

such findings (Table 3) are encountered,it may be reasonable to perform morefrequent surveillance (eg, weekly insteadof every 2 weeks) for TTTS. Velamentousplacental cord insertion (Figure 6) hasbeen found in approximately one thirdof placentas with TTTS.28 Intertwin

embrane folding (Figure 7) has beenssociated with development of TTTS inore than a third of cases.42 The clinical

utility of the sonographic findings listedin Table 3 has not been prospectivelyevaluated, and several require Dopplerevaluation not typically performed in

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tations. Thus, while they are associatedwith TTTS and may potentially im-prove TTTS detection, they are notspecifically recommended as part ofroutine surveillance.

In addition to TTTS, MCDA gesta-tions are at risk for discordant twingrowth or discordant IUGR. When com-pared to MCDA twins with concordantgrowth, velamentous placental cord in-sertion (22% vs 8%, P � .001) and un-qual placental sharing (56% vs 19%,� .0001) are seen more commonly in

ases with discordant growth.50 Unequallacental sharing occurs in about 20% ofCDA gestations and can coexist with

TTS, complicating the diagnosis andanagement of the pregnancy. For ex-

mple, abnormal umbilical artery wave-orms in MCDA twins may representlacental insufficiency, but may also beecondary to the presence of intertwinnastomoses and changes in vascular re-ctivity typical of TTTS (Figure 3). Over-ll, the development of abnormal end-iastolic flow in the umbilical artery,specially absent or reversed, has beenssociated with later deterioration ofetal testing necessitating delivery in

CDA twins,51,52 but latency betweenDoppler and other fetal testing changesis increased in these gestations com-pared to singletons.53 Frequent, eg,wice weekly, fetal surveillance is sug-ested for MCDA pregnancies with ab-ormal umbilical artery Doppler onceiability is reached.52

Question 5. Is there a role for fetalechocardiography in TTTS?(Levels II and III)Screening for congenital heart diseasewith fetal echocardiography is warrantedin all monochorionic twins as the risk ofcardiac anomalies is increased 9-fold inMCDA twins and up to 14-fold in casesof TTTS, above the population preva-lence of approximately 0.5%.54 Specifi-cally, the prevalence of congenital car-diac anomalies has been reported to be2% in otherwise uncomplicated MCDAgestations and 5% in cases of TTTS, par-ticularly among recipient twins.55 Al-though many cases are minor septal de-fects, an increase in right ventricular
outflow tract obstruction has also been
reported.55 It is theorized that the abnor-al placentation that occurs in mono-

horionic twins, particularly in cases thatevelop TTTS, contributes to abnormal

etal heart formation.54

The functional cardiac abnormalitiesthat complicate TTTS occur primarily inrecipient twins. Volume overload causesincreased pulmonary and aortic veloci-ties, cardiomegaly, and atrioventricularvalve regurgitation (Figure 8). Overtime, recipient twins can develop pro-gressive biventricular hypertrophy anddiastolic dysfunction as well as poorright ventricular systolic function thatcan lead to functional right ventricularoutflow tract obstruction and pulmonicstenosis (Figure 9).54,56 The develop-ment of right ventricular outflow ob-struction, observed in close to 10% of allrecipient twins, is likely multifactorial, aconsequence of increased preload, after-load, and circulating factors such as renin,angiotensin, endothelin, and atrial andbrain natriuretic peptides.57-59 The cardio-ascular response to TTTS contributes tohe poor outcome of recipient twins whileecipients with normal cardiac functionave improved survival.60

A functional assessment of the fetalheart may be useful in identifying casesthat would benefit from therapy and inevaluating the response to treatment.The myocardial performance index orTei index, an index of global ventricularperformance by Doppler velocimetry, isa measure of both systolic and diastolic

TABLE 3First- and second-trimester sonograssociated with twin-twin transfusio

First-trimester findings..........................................................................................................

Crown-rump length discordance43

..........................................................................................................

Nuchal translucency �95th percentile42,4

..........................................................................................................

Reversal or absence of ductus venosus A-...................................................................................................................

Second-trimester findings..........................................................................................................

Abdominal circumference discordance43

..........................................................................................................

Membrane folding28,42

..........................................................................................................

Velamentous placental cord insertion (don..........................................................................................................

Placental echogenicity (donor portion hype...................................................................................................................


function,61 and has been used to moni-

JANUARY 2013 A

tor fetuses with TTTS.62 Donor twinsith TTTS tend to have normal cardiac

unction, whereas recipient twins may de-elop ventricular hypertrophy (61%),trioventricular valve regurgitation (21%),nd abnormal right ventricular (50%) oreft ventricular (58%) function.11,58 Over-

all, two thirds of recipient twins show di-astolic dysfunction, as indicated by aprolonged ventricular isovolumetric re-laxation time, which is associated withan increased risk of fetal death.58

Although fetal cardiac findings are notofficially part of the TTTS staging sys-tem, many centers routinely perform fe-tal echocardiography in cases of TTTSand have observed worsening cardiacfunction in advanced stages.11 However,cardiac dysfunction can also be detectedin up to 10% of apparently early-stageTTTS.11 It has been theorized that theearly diagnosis of recipient twin cardiomy-opathy may identify those MCDA gesta-tions that would benefit from early inter-vention. In summary, scoring systems thatinclude cardiac dysfunction have been de-veloped, but their usefulness to predictoutcome in TTTS remains controver-sial.63,64 Further evaluation of functionalfetal echocardiography as a tool for deci-sion-making about intervention and man-agement in TTTS is needed.

Question 6. What managementoptions are available for TTTS?(Levels I, II, and III)The management options described for

hic findingsyndrome

..................................................................................................................

..................................................................................................................

discordance �20% between twins45,46

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amnioreduction, intentional septostomyof the intervening membrane, fetoscopiclaser photocoagulation of placental anas-tomoses, and selective reduction. The in-

FIGURE 6Abnormal placental cord insertion

A, Velamentous or membranous placental cordwin detected by color Doppler. B, Velamentoudentification of anastomosis (arrows) passing bef twins.

Reproduced with permission from Simpson.1


terventions that have been evaluated in


randomized controlled trials (RCTs) in-clude intentional septostomy of the inter-vening membrane to equalize the fluid inboth sacs, amnioreduction of the excess

rtion (PCI) (arrow) of monochorionic diamnioticCI confirmed on examination of placenta withth separating membrane and joining circulations

013.

fluid in the recipient’s sac, and laser abla-

NUARY 2013

ion of placental anastomoses. Thereave been 3 randomized trials designedo evaluate some of the different treat-

ent modalities for TTTS, all of whichere terminated prior to recruitment of

he planned subject number after in-erim analyses, as discussed below.65-67

Despite the limitations and early termi-nation of these clinical trials, they repre-sent the best available data upon which tojudge the various treatments for TTTS.Consultation with a maternal-fetal medi-cine specialist is recommended, particu-larly if the patient is at a gestational age atwhich laser therapy is potentially an op-tion. In evaluating the data, considerationsinclude the stage of TTTS, the details of theintervention, and the perinatal outcome.The most important outcomes reportedare overall perinatal mortality, survival ofat least 1 twin, and, if available, long-termoutcomes of the babies, including neuro-logic outcome. Extensive counselingshould be provided to patients with preg-nancies complicated by TTTS, includingnatural history of the disease, as well asmanagement options and their risks andbenefits.

Expectant management involves nointervention. This natural history ofTTTS, also called conservative manage-ment, has limited outcome data accord-ing to stage, particularly for advanceddisease (Table 2). It is important that thelimitations in the available data are dis-cussed with the patient with TTTS, andcompared with available outcome datafor interventions.

Amnioreduction involves the removalof amniotic fluid from the polyhydram-niotic sac of the recipient. It is usuallydone only when the MVP is �8 cm, withan aim to correct it to a MVP of �8 cm,often to �5 cm or �6 cm.65-67 Usuallyn 18-65 or 2067-gauge needle is used.ome practitioners use aspiration withyringes, while some use vacuum con-ainers.66 Amnioreduction can be per-

formed either as a 1-time procedure, asat times this can resolve stage I or IITTTS, or serially, eg, every time the MVPis �8 cm. It can be performed any time�14 weeks. Amnioreduction is hypoth-esized to reduce the intraamniotic andplacental intravascular pressures, poten-

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and/or to possibly reduce the incidenceof preterm labor and birth related topolyhydramnios. Amnioreduction maybe used also �26 weeks, particularly incases with maternal respiratory distressor preterm contractions from polyhy-dramnios.68 Amnioreduction has beenassociated with average survival rates of50%, with large registries reporting 60-65% overall survival.69,70 However, se-ial amnioreduction is often necessary,nd repeated procedures increase the like-ihood of complications such as pretermremature rupture of the membranes, pre-erm labor, abruption, infection, and fetaleath.71 Another consideration is that any

nvasive procedure prior to fetoscopyay decrease the feasibility and success

f laser due to bleeding, chorioamnioneparation, inadvertent septostomy, or

embrane rupture.Septostomy involves intentionally

uncturing with a needle the amnioticembranes between the 2 MCDA sacs,

heoretically allowing equilibration ofmniotic fluid volume in the 2 sacs.66 In

the 1 randomized trial in which it wasevaluated, the intertwin membrane waspurposefully perforated under ultra-sound guidance with a single punctureusing a 22-gauge needle.66 This was usu-ally introduced through the donor’s twingestational sac into the recipient twin’samniotic cavity. If reaccumulation ofamniotic fluid in the donor twin sac wasnot seen in about 48 hours, a repeat sep-tostomy was undertaken.66 Intentionaleptostomy is mentioned only to notehat it has generally been abandoned as areatment for TTTS. It is believed to offero significant therapeutic advantage,nd may lead to disruption of theembrane and a functional monoam-

iotic situation. A randomized trial ofmnioreduction vs septostomy endedfter an interim analysis found that theate of survival of at least 1 twin wasimilar between the 2 groups, and thatecruitment had been slower than an-icipated66 (Table 4). In all, 97% of the

enrolled pregnancies had stages I-IIITTTS, and results were not otherwisereported by stage. In 40% of the septo-stomy cases, additional procedureswere needed. No data on neurologic
outcome are available.66
Laser involves photocoagulating thevascular anastomoses crossing from oneside of the placenta to the other. This isusually performed by placing a sheathand passing an endoscope under ultra-sound guidance. Ultrasound is also usedto map the vasculature to determine theplacental angioarchitecture. The pri-mary theoretical advantage of laser coag-ulation is that it is designed to interruptthe placental anastomoses that give riseto TTTS. The goal of laser ablation is tofunctionally separate the placenta into 2

FIGURE 7Membrane folding

embrane folding (arrow) suggestive of discordanwin gestation.eproduced with permission from Simpson.1

MFM. Twin-twin transfusion syndrome. Am J Obstet Gyne

FIGURE 8Cardiac dysfunction in recipient tw

olor flow imaging demonstrating forward flow aricuspid regurgitation (arrow) during systole in reproduced with permission from Simpson.1


JANUARY 2013 A

regions, each supplying one of the twins.This unlinking of the circulations of thetwins is often referred to as “dichorion-ization” of the monochorionic placenta.Adequate visualization of the vascularequator that separates the cotyledons ofone twin from the other is critical for la-ser photocoagulation. Selective coagula-tion of AV as well as AA and VV anasto-moses is preferred over nonselectiveablation of all vessels crossing the sep-arating membrane as it appears tolead to fewer procedure-related fetal

niotic fluid volume in monochorionic diamniotic

013.

ss atrioventricular valves in diastole and severeient twin.

013.

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losses.72 Sequential coagulation of theonor artery to recipient vein followedy recipient artery to donor vein mayheoretically allow some return of fluidrom the recipient to the donor prior toevering other connections.73,74 Crite-ia for laser have included MCDAregnancies between about 15-26eeks with the recipient twin havingVP �8.0 cm at �20 weeks or �10.0

m at �20 weeks and a distended fetalladder, and donor twin having MVP

FIGURE 9Recipient twin cardiomyopathy

Reproduced with permission from Simpson.1


TABLE 4Randomized trial of septostomy vs

Variable

Mean gestational age at delivery, wk...................................................................................................................

Survival of at least 1 twin at 28 d of age...................................................................................................................

All perinatal deaths up to 28 d of age...................................................................................................................

SMFM. Twin-twin transfusion syndrome. Am J Obstet Gynec

10 American Journal of Obstetrics & Gynecology J

2.0 cm in 1 trial,65 and MCDA preg-ancies at �24 weeks with the recipi-nt twin having MVP �8 cm, and do-or twin having MVP �2 cm andonvisualized fetal bladder in thether.67 There is insufficient evidenceo recommend management in MCDAairs with TTTS in higher-order mul-iple gestations, but laser has been pro-osed as feasible and effective.75

Selective reduction involves purpose-fully interrupting umbilical cord blood

013.

nioreduction57

tostomy35

Amnioreductionn � 36 P value

29.5 .24..................................................................................................................

(28/35) 78% (28/36) .82..................................................................................................................

(21/70) 36% (26/72) .40..................................................................................................................

sol 2013.

ANUARY 2013

flow of 1 twin, causing the death of thistwin, with the purpose of improving theoutcome of the other surviving twin.Usually the cord occlusion is performedwith radiofrequency ablation or cord co-agulation, but other procedures havebeen employed.76 Obviously this optionan be associated with a maximum of0% overall survival, so, if ever consid-red, it is usually reserved for stages III orV TTTS only.

Question 7. What are the managementrecommendations according to stage?(Levels I, II, and III)Stage IThere is no randomized trial specificallyincluding stage I TTTS patients managedwithout interventions, ie, expectantly orconservatively managed. Patients withstage I TTTS are often managed expec-tantly, as over three-fourths of cases re-main stable or regress spontaneously (Fig-ure 10).19-21 Because stage I TTTS

rogresses to more advanced TTTS in 10-0% of cases, interventions have beenvaluated.

Stages I and II TTTS have been shown toegress following amnioreduction in up to0-30% of cases, a rate that is not signifi-antly different than with expectant man-gement, especially for stage I.20,66

Laser has been studied for stage I TTTSin only 6 patients in the Eurofetus trial,65

and no patients in the Eunice KennedyShriver National Institute of ChildHealth and Human Development(NICHD) RCT.67 Only limited data existfrom nonrandomized studies.8,9,20,39 In

metaanalysis of stage I TTTS treatedith laser photocoagulation, survival ofoth twins occurred in 45 of 60 twinairs (75%), with an 83% overall sur-ival, rates that are similar to other man-gement strategies including expectantanagement, therefore providing no

dded benefit.9 In a review of the litera-ture including only stage I TTTS, theoverall survival rates were 86% after ex-pectant management, 77% after am-nioreduction, and 86% after laser ther-apy, leading the investigators to suggestthat conservative management in stage ITTTS is a reasonable option.20 The pro-ression to higher stage was only 15% for

col 2

am

Sepn �

30.7.........

80%.........

30%.........

tage I after expectant management, and


survival was similar if laser was em-ployed as first- or second-choice therapyin this review.20 Further studies areneeded to determine the optimal man-agement of stage I TTTS.

Stages II, III, and IVCurrently, fetoscopic laser photocoagu-lation of placental anastomoses is con-sidered by most experts to be the bestavailable approach for stages II, III, andIV TTTS in continuing pregnancies at�26 weeks (Figure 10), but metaanalysisdata show no survival benefit, and thelong-term neurologic outcomes in Euro-fetus were not different than in nonlaser-treated controls. There is no randomizedtrial specifically including a group ofTTTS patients with stages II, III, and IV,managed without interventions, ie, ex-pectantly. Data on natural history forstage �II are not available (Table 2).

Two randomized trials have evaluatedthe effectiveness of laser therapy in preg-nancies complicated by TTTS. In thefirst, called the Eurofetus trial, inclusioncriteria were MCDA pregnancies be-tween 15 and 25 6/7 weeks with the re-cipient twin having MVP �8.0 cm at�20 weeks or �10.0 cm at �20 weeksand a distended fetal bladder, and donortwin having MVP �2.0 cm. A total of 142women were randomized from 3 centersin Europe (90% in France) to either se-lective laser photocoagulation or serialamnioreduction. The trial was stoppedafter an interim analysis demonstratedlaser to be superior to amnioreductionwith improved perinatal survival andfewer short-term neurologic abnormali-ties. Over 90% of the patients random-ized had either stage II or III TTTS (6with stage I; only 2 with stage IV). Thelaser group also did have an initial am-nioreduction at laser surgery. Elevenwomen (16%) vs no women (0%) hadvoluntary termination of pregnancy af-ter being randomized to amnioreduc-tion and laser, respectively. Selected re-sults are shown in Table 5.65,77

In the second trial, sponsored by theNICHD, inclusion criteria were MCDApregnancies at �24 weeks with the recip-ient twin having MVP �8 cm, and donortwin having MVP �2 cm and nonvisu-
alized empty fetal bladder. Stage I TTTS
was therefore not included. A single di-agnostic and therapeutic qualifying am-nioreduction was performed on all preg-nancies. This trial was also terminatedearly due to poor recruitment as well asincreased neonatal mortality of recipienttwins treated with laser therapy.67

Ninety percent of the patients random-

FIGURE 10Algorithm for management of TTTS

MCDA pregnancy witMVP <8 cm in othe

Do staging (Table 1)UA Do

Stage I Stag

Counseling. Consider expectant management,

with fetal bladder, UA Doppler, and hydrops

ultrasonographic checks at least once per week

Counselreferral tfor laser

16-25 6unableeligibil

consider a

CDA, monochorionic diamniotic; MVP, maximum vertical pocke


TABLE 5Randomized trial of laser photocoavs amnioreduction (Eurofetus)65,77

Variable

Laprn �

Median gestational age at delivery, wk 33...................................................................................................................

Survival of at least 1 twin at 6 mo of age 76...................................................................................................................

All perinatal deaths up to 6 mo of age 44...................................................................................................................

Cystic periventricular leukomalaciaat 6 mo

6

...................................................................................................................

Alive and free of neurologiccomplications at 6 mo

52

...................................................................................................................

Normal neurologic development at 6 yb 82...................................................................................................................a Of women in amnioreduction group, 11 (16%) had voluntary

children delivered in France and still alive at 6 mo of age.

SMFM. Twin-twin transfusion syndrome. Am J Obstet Gyneco

JANUARY 2013 Am

ized had either stage II or III TTTS.Three US centers participated (Chil-dren’s Hospital of Philadelphia; Univer-sity of California, San Francisco; andCincinnati Children’s Hospital MedicalCenter). The laser group also had an ini-tial amnioreduction at laser surgery. Se-lected results are shown in Table 6.67 In-

VP <2 cm in 1 sac and c: Diagnosis = TTTS

ck fetal bladder, er

III, IV Stage V

Consider tal center tment at eeks; if

outside riteria, oreduc�on

Counsel regarding co-twin 10% risk of death

and 10-30% risk of neurologic

complica�ons. Consider expectant

management.

S, twin-twin transfusion syndrome; UA, umbilical artery.

013.

lation

, n � 72ancies/44 twins

Amnioreduction,n � 70 pregnancies/n � 140 twinsa P value

29.0a .004..................................................................................................................

55/72) 56% (36/70)a .009..................................................................................................................

63/144) 61% (86/140)a .01..................................................................................................................

8/144) 14% (20/140) .02

..................................................................................................................

75/144) 31% (44/140) .003

..................................................................................................................

60/73) 70% (33/47) .12..................................................................................................................

ination of pregnancy between 21-25 wk; b Includes only

h Mr sa

: cheppl

e II,

ing. o fe trea/7 w or ity cmni

M t; TTT

S col 2

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.3.........

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term

l 2013.

erican Journal of Obstetrics & Gynecology 11

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fant outcome is available for this trialonly up to 30 days of age. While the sur-vival of at least 1 twin was comparable tothe Eurofetus trial for the laser groups(65% in NICHD vs 76% Eurofetus), thisoutcome in the amnioreduction groupswas better in the NICHD (75%) com-pared to the Eurofetus study (56%). Thebetter NICHD amnioreduction resultsmay be due to the standardized aggres-sive protocol used (performed everytime the MVP was �8 cm). In contrast,the less favorable NICHD laser resultsmay have been due to the severity ofTTTS cardiomyopathy, especially in therecipients; the fact that there were morestage IV TTTS cases in NICHD (n � 4)han in Eurofetus (n � 2); and that thepper gestational age for inclusion waslso different in NICHD (�24 weeks) vs Eu-ofetus (�26 weeks).65,67 Recipient twin

ortality was significantly higher in theaser (70%) than the amnioreduction35%) group (Table 6).67 In a meta-nalysis of these 2 trials, overall deathas not significantly different between

aser and amnioreduction (risk ratio,.81; 95% confidence interval, 0.65–.01).71 These data on laser apply mostly

to stage II and III TTTS, given the verylimited number of stage I or IV TTTSincluded in the 2 trials.65,67

In summary, laser therapy has been as-sociated with some perinatal benefits in 1European trial, which had some limita-tions, while no benefits were seen in an-other smaller US trial.

Like all invasive procedures, laser hasbeen associated with complications, in-

TABLE 6Randomized trial of laser photocoavs amnioreduction (NICHD-sponsor

Variable

Laprn

Mean gestational age at delivery, wk 30...................................................................................................................

Survival of at least 1 twin at 30 d of age 65...................................................................................................................

All perinatal deaths up to 30 d of age 55...................................................................................................................

Recipient twin fetal mortality 70...................................................................................................................

NICHD, Eunice Kennedy Shriver National Institute of Child Hea


cluding preterm premature rupture of i


the membranes, preterm delivery, amni-otic fluid leakage into the maternal peri-toneal cavity, vaginal bleeding and/orabruption, and chorioamnionitis.78 Fe-toscopy equipment is of larger gaugethan the spinal needles used for am-nioreduction or septostomy and, as a re-sult, the risks of complications are up to3-fold higher.65 In the Eurofetus trial,the overall risk for most complicationswas about 3%.65 Maternal and perinatalisks can be particularly high in inexpe-ienced hands. Despite these risks, feto-copic laser photocoagulation appears toe the optimal treatment for stage II-IVTTS. However, it is important to re-ember that even with laser therapy, in-

act survival of both twins with TTTS isnly about 50% (Table 7).74,78-82

Expectant management and amniore-duction remain 2 options in cases ofTTTS stage �I at �26 weeks of gesta-tion, in which the patient does not havethe ability to travel to a center that per-forms fetoscopic laser photocoagulation.

In cases complicated by severe un-equal placental sharing with marked dis-cordant growth and IUGR, major mal-formations affecting 1 twin, or evidenceof brain injury either before or subse-quent to laser, selective reduction bycord occlusion76 or by termination of thentire pregnancy may be reasonableanagement choices for the patient and

er family �24 weeks’ gestation.

tage Vn cases of stage V TTTS, ie, death of 1win, no intervention has been evaluated

lation)67

, n � 20ancies/0 twins

Amnioreduction,n � 20 pregnancies/n � 40 twin P value

30.2 NS..................................................................................................................

13/20) 75% (15/20) .73..................................................................................................................

22/40) 40% (16/40) .18..................................................................................................................

14/20) 35% (7/20) .03..................................................................................................................

nd Human Development; NS, nonsignificant.

ol 2013.

n randomized trials to try to ameliorate

ANUARY 2013

utcome. As stated above, in cases ofeath of 1 MCDA twin, the risks to theotwin included a 10% risk of death and0-30% risk of neurologic complicationsFigure 10).25-27 It may be that the ab-ormal neurologic outcome in someurvivors of TTTS is more correlated tohether or not there was demise of a cot-in, than the actual modality used to

reat the condition.83 It is well recog-nized that death of 1 twin of a mono-chorionic pair can result in periven-tricular leukomalacia, intraventricularhemorrhage, hydrocephaly, and por-encephaly. Prior laser ablation appearsto improve neurologic outcomes in thesurvivor if there is a cotwin demise.84

Question 8. After in utero laser forTTTS, what is the expected survivaland long-term outcome of thetwins? (Levels II and III)In general, overall survival rates of 50-70% can be expected after fetoscopic la-ser for the treatment of TTTS.71 Overall

erinatal survival of fetuses with TTTSreated with laser was 56% in the Euro-etus trial at 6 months of age,65 and 45%n the NICHD trial at 30 days67 (Tables 5

and 6, respectively). The Eurofetus trialreported an 86% survival rate of at least 1fetus for combined stage I and II diseasetreated with laser, decreasing to 66% forcombined stage III and IV.65 In recentnonrandomized large series, summariz-ing �1000 cases of TTTS (about 86%with stages II and III) treated with laser,the overall perinatal survival was about65% (Table 7). Given publication bias,these data probably represent the bestcurrent possible outcomes with thisprocedure.

Although the risk of membrane rup-ture may be as low as 10% in experiencedcenters, there remains a 10-30% proce-dure-associated fetal loss with la-ser.65,72,80,85 Both double and single fetal

emise are common complications indvanced stages of TTTS treated with la-er (Table 7). In a multicenter observa-ional study, fetal demise occurred in4% of donors and in 17% of recipientsfter laser.86 Survival of 1 or 2 fetuses af-

ter laser may depend on coexisting un-equal placental sharing that may not be

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scopy. Preoperative IUGR with absent orreversed end-diastolic flow in the umbil-ical artery has a 20-40% increased risk ofpostoperative donor demise.86,87 Recip-ent twin demise after laser is more com-

on when the recipient has IUGR, re-ersed a-wave in the ductus venosus, orydrops.86 Improved recipient twin sur-

vival has been reported with the mater-nal administration of nifedipine 24-48hours prior to laser photocoagulation incases of TTTS cardiomyopathy,88 but

ore data are needed to suggest its use inhis clinical situation. After successful la-er photocoagulation, the cardiac func-ion of recipient twins tends to normal-ze in about 4 weeks.89 Pulmonic valvebnormalities, affecting about 20% of re-ipient twins with advanced TTTS, havelso been observed to improve after laserith less than a third of surviving twinsaving persistent pulmonic valve defectsequiring treatment after birth.90 Over-ll, 87% of postlaser recipient twins whourvived were reported to have normalchocardiograms at a median age justnder 2 years.59

Although procedure-related fetal loss isa recognized complication of fetoscopic la-ser photocoagulation, survival with neuro-logic handicap is also a serious long-termsequela of TTTS, with or without treat-ment. While the gestational age at deliveryis a significant risk factor for adverse neu-rologic outcome, initial studies suggestedthat neurologic outcomes may be betterfor those cases managed with laser photo-coagulation, compared to amnioreduc-tion. Infants in the laser group of the Euro-fetus trial had a lower incidence of cysticperiventricular leukomalacia and weremore likely to be free of neurologic com-plications at 6 months of age compared tothose treated with amnioreduction (Table6).65 However, 6-year follow-up of 120hildren from this trial found that laserherapy conferred no significant benefit inerms of difference in major neurologicandicap among TTTS survivors treatedith laser vs amnioreduction.77 Another

ecent study also reported no difference ineurodevelopmental outcome at 2 years ofge among donors and recipients treatedith laser or amnioreduction, although

hey did observe a trend of increased major
eurologic impairment in survivors after
T P S V . H . Y . H . Q . M . T . G R a

JANUARY 2013 American Journal of Obstetrics & Gynecology 13

amfisacm

tbcst

cscusi

o

ynec


amnioreduction compared to thosetreated with laser (9.5% vs 4.6%).91

Overall, rates of long-term neurologicsequelae in laser-treated stage I TTTS arereported to be about �3%, with rates ofabout 5-20% in survivors of any stageTTTS (Table 8).83,91-94 The risk of ab-normal neurodevelopment seems to besimilar in donor and recipient survivors,and not drastically different betweenthose treated with laser or amnioreduc-tion. Antenatally acquired severe brainlesions, including cystic periventricularleukomalacia and grade-3 or -4 intra-ventricular hemorrhage, affect 10% ofTTTS compared to 2% of MCDA twinswithout TTTS (P � .02); this differencewas seen to persist in findings seen oncranial ultrasounds at the time of hospi-tal discharge (14% vs 6%, P � .04).95

Other risk factors for neurodevelopmen-tal impairment in TTTS survivors are ad-vanced gestational age at laser surgery,low birth weight, and severe TTTS.92

Both ultrasound and magnetic reso-nance imaging (MRI) can be used toevaluate abnormalities of the fetal brain.In general, fetal MRI to evaluate corticaldevelopment and assess for ischemic in-jury is best in the third trimester. Follow-ing single twin demise in a MCDA gesta-

TABLE 8Long-term neurologic outcome of ltwin-twin transfusion syndrome su

Study nApproximate age atassessment, mo

Node

Sutcliffeet al,93

2001

66 24 —

...................................................................................................................

Baneket al,83

2003

89 22 78

...................................................................................................................

Graefet al,94

2006

167 38 86

...................................................................................................................

Lenclenet al,91

2009

88 24 88

...................................................................................................................

Loprioreet al,92

2009

278 24 82

...................................................................................................................


tion, neurologic injury, when present in


the surviving twin, may be detected byultrasound in about 1-2 weeks, and byMRI as early as 1-2 days after the demiseof the other twin.96,97 Routine neuroim-ging with MRI cannot yet be recom-ended given the limited data on bene-

t, although this has been suggested byome authors for TTTS both prior to andfter therapeutic interventions, or inases complicated by single twin de-ise.84,85,97,98 Follow-up studies of all

survivors of TTTS are critical to deter-mine accurate long-term outcomesand stage-specific rates of neurologichandicap of these complicated MCDApregnancies.

In summary, even with the laser treat-ment option available, TTTS is still a severecondition in terms of perinatal outcomes.Given the 30-50% chance of overall peri-natal death and 5-20% chance of neuro-logic handicap long-term, twin death orneurologic handicap is the outcome in upto two thirds of laser-treated TTTS.99

Question 9. What antenatal monitoringshould be suggested for pregnanciescomplicated by TTTS? (Levels II and III)There are no randomized trials to evalu-ate the effectiveness of antenatal moni-toring for pregnancies complicated by

r-treatedvors

alopment

Majorneurologicabnormalities

Minorneurologicabnormalities

9% —

..................................................................................................................

11% 11%

..................................................................................................................

6.0% 7.2%

..................................................................................................................

4.6% 6.8%

..................................................................................................................

18% —

..................................................................................................................

ol 2013.

TTTS. Weekly monitoring of the umbil- p

ANUARY 2013

ical artery Doppler flow and MVP of am-niotic fluid of each fetus may be consid-ered. The evidence for effectiveness ofserial (eg, weekly or twice/wk) nonstresstests, biophysical profiles, and other an-tenatal testing modalities is insuffi-cient to make a recommendation, butthese tests can be considered.

One reason for surveillance, even fol-lowing laser therapy, is that not all anas-tomoses are ablated at the time of la-ser.73,100 Residual anastomoses, eitherinitially undetected, missed, or revascu-larized after laser, have been observed inup to a third of cases.101,102 Placentalcasting has also demonstrated the pres-ence of deep, atypical AV anastomoses be-neath the chorionic plate that would not bevisible by fetoscopy.103 Failure to coagulateall AV anastomoses can lead to persistent,recurrent or reversed TTTS.103 Persistentor recurrent TTTS has been reported in14% of cases postlaser and reversed TTTS,with the recipient becoming anemic andthe donor polycythemic, in 13% ofcases.104,105 While TAPS can occur spon-taneously in a MCDA gestation, it is aknown iatrogenic complication of laser.

Screening by transvaginal ultrasoundfor short cervical length in TTTS caseshas also been proposed, as this is associ-ated with preterm birth, a known com-plication of TTTS.106 As there are no in-erventions shown to improve outcomeased on short transvaginal ultrasoundervical length in TTTS cases, thiscreening cannot be recommended athis time.107

Question 10. When should patientswith TTTS be delivered?(Levels II and III)MCDA pregnancies complicated byTTTS are at increased risk of severalcomplications, including but not limitedto preterm birth, fetal demise, and cere-bral injury.108-110 Because of the in-reased risk of preterm birth, 1 course ofteroids for fetal maturation should beonsidered at 24 to 33 6/7 weeks, partic-larly in pregnancies complicated bytage �III TTTS, and those undergoingnvasive interventions.

There are no clinical trials regardingptimal timing of delivery for TTTS

aservi

rmvel

.........

%

.........

.8%

.........

.6%

.........

%

.........

regnancies. This depends on several

leddpdmTsicssda

Ll1

Ll2

Ll3

Ll4

Ll5

Ll6

Ll7

Ll8

Ll9

Pf


factors, including disease stage and se-verity, progression, effect of interven-tions (if any), and results of antenataltesting. Recommendations regardingtiming of delivery with TTTS vary, withsome endorsing planned preterm deliv-ery as early as 32-34 weeks, and othersindividualizing care and allowing gesta-tion to progress to 34-37 weeks, particu-larly in cases of mild disease (eg, stages Iand II) with reassuring surveillance.

The median gestational age at delivery inthe major trials and case series of laser-treated TTTS has been about 33-34 weeks(Table 7).65,67,74,80-82 Cases treated withaser generally have more advanced dis-ase, and they may be at risk for earlyelivery due to both TTTS and proce-ure-related complications. However,rematurity has been identified as an in-ependent risk factor for neurodevelop-ental impairment in the setting ofTTS.92 Given the spectrum of disease as-

ociated with TTTS, many variables factornto decisions about timing of delivery, in-luding disease stage, progression, re-ponse to treatment, fetal growth, and re-ults of antenatal surveillance. Delayingelivery until 34-36 weeks may be reason-ble even after successful laser ablation.

RECOMMENDATIONS

evels II and III evidence,evel B recommendation. The diagnosis of TTTS requires 2 cri-

teria: (1) the presence of a MCDApregnancy; and (2) the presence ofoligohydramnios (defined as a MVPof �2 cm) in one sac, and of polyhy-dramnios (a MVP of �8 cm) in theother sac.

evels II and III evidence,evel B recommendation. The Quintero staging system appears

to be a useful tool for describing theseverity of TTTS in a standardizedfashion.

evels II and III evidence,evel B recommendation. Serial sonographic evaluations about

every 2 weeks, beginning usually
around 16 weeks of gestation, until
delivery, should be considered for alltwins with MCDA placentation.

evels II and III evidence,evel B recommendation. Screening for congenital heart disease

is warranted in all monochorionictwins, in particular those complicatedby TTTS.

evels II and III evidence,evel B recommendation. Extensive counseling should be pro-

vided to patients with pregnanciescomplicated by TTTS including nat-ural history of the disease, as well asmanagement options and their risksand benefits. Over three fourths ofstage I TTTS cases remain stable orregress without invasive interven-tions. The natural history of advanced(eg, stage �III) TTTS is bleak, with areported perinatal loss rate of 70-100%, particularly when it presents�26 weeks. The management op-tions available for TTTS include ex-pectant management, amnioreduc-tion, intentional septostomy of theintervening membrane, fetoscopic la-ser photocoagulation of placentalanastomoses, selective reduction, andpregnancy termination.

evels II and III evidence,evel B recommendation. Patients with stage I TTTS may often

be managed expectantly, as the natu-ral history perinatal survival rate isabout 86%.

evels I and II evidence,evel B recommendation. Fetoscopic laser photocoagulation

of placental anastomoses is consid-ered by most experts to be the bestavailable approach for stages II, III,and IV TTTS in continuing preg-nancies at �26 weeks, but the meta-analysis data show no significantsurvival benefit, and the long-termneurologic outcomes in the Eurofe-tus trial were not different than innonlaser-treated controls. Laser-treated TTTS is still associated with a30-50% chance of overall perinataldeath and a 5-20% chance of long-term
neurologic handicap. s
JANUARY 2013 Am

evels I and II evidence,evel B recommendation. Steroids for fetal maturation should

be considered at 24 to 33 6/7 weeks,particularly in pregnancies compli-cated by stage �III TTTS, and thoseundergoing invasive interventions.

evel III evidence,evel C recommendation. Optimal timing of delivery for TTTS

pregnancies depends on several factors,including disease stage and severity,progression, effect of interventions (ifany), and results of antenatal testing.Timing delivery at around 34-36 weeksmay be reasonable in selected cases.

This opinion was developed by theublications Committee of the Society

or Maternal-Fetal Medicine with the as-

Quality of evidence

The quality of evidence for each includedarticle was evaluated according to thecategories outlined by the USPreventative Services taskforce:

I Properly powered and conducted RCT;well-conducted systematic review ormetaanalysis of homogeneous RCTs.

.........................................................................................................

II-1 Well-designed controlled trial withoutrandomization.

.........................................................................................................

II-2 Well-designed cohort or case-controlanalytic study.

.........................................................................................................

II-3 Multiple time series with or withoutthe intervention; dramatic resultsfrom uncontrolled experiments.

.........................................................................................................

III Opinions of respected authorities,based on clinical experience; descrip-tive studies or case reports; reports ofexpert committees.

Recommendations are gradedin the following categories:

Level AThe recommendation is based on good andconsistent scientific evidence.

Level BThe recommendation is based on limited orinconsistent scientific evidence.

Level CThe recommendation is based on expertopinion or consensus.

istance of Lynn L. Simpson, BSc, MSc,



MD, and was approved by the ExecutiveCommittee of the Society on September20, 2012. Dr Simpson, and each memberof the Publications Committee (Vin-cenzo Berghella, MD [Chair], SeanBlackwell, MD [Vice-Chair], BrennaAnderson, MD, Suneet P. Chauhan,MD, Joshua Copel, MD, Jodi Dashe,MD, Cynthia Gyamfi, MD, Donna John-son, MD, Sara Little, MD, Kate Menard,MD, Mary Norton, MD, George Saade,MD, Neil Silverman, MD, HyagrivSimhan, MD, Joanne Stone, MD, AlanTita, MD, PhD, Michael Varner, MD,Ms Deborah Gardner) have submitted aconflict of interest disclosure delineatingpersonal, professional, and/or businessinterests that might be perceived as a realor potential conflict of interest in rela-tion to this publication. f

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restriction in monochorionic pregnanciesaccording to umbilical artery Doppler flow in thesmaller twin. Ultrasound Obstet Gynecol 2007;30:28-34. Level II-3.53. Vanderheyden TM, Fichera A, Pasquini L, etal. Increased latency of absent end-diastolicflow in the umbilical artery of monochorionictwin fetuses. Ultrasound Obstet Gynecol 2005;26:44-9. Level II-2.54. Bahtiyar MO, Dulay AT, Weeks BP, Fried-man AH, Copel JA. Prevalence of congenitalheart defects in monochorionic/diamniotic twingestations: a systematic literature review. J Ul-trasound Med 2007;26:1491-8. Level II-1.55. Lopriore E, Bokenkamp R, Rijlaarsdam M,Sueters M, Vandenbussche FP, Walther FJ. Con-genital heart disease in twin-to-twin transfusionsyndrome treated with fetoscopic laser surgery.Congenit Heart Dis 2007;2:38-43. Level II-2.56. Karatza AA, Wolfenden JL, Taylor MJ, WeeL, Fisk NM, Gardiner HM. Influence of twin-twintransfusion syndrome on fetal cardiovascularstructure and function: prospective case-con-trol study of 136 monochorionic twin pregnan-cies. Heart 2002;88:271-7. Level II-2.57. Bajoria R, Sullivan M, Fisk NM. Endothelinconcentrations in monochorionic twins with se-vere twin-twin transfusion syndrome. Hum Re-prod 1999;14:1614-8. Level II-3.58. Barrea C, Alkazaleh F, Ryan G, et al. Prena-tal cardiovascular manifestations in the twin-to-twin transfusion syndrome recipients and theimpact of therapeutic amnioreduction. Am JObstet Gynecol 2005;192:892-902. Level II-2.59. Herberg U, Gross W, Bartmann P, BanekCS, Hecher K, Breuer J. Long-term cardiac fol-low up of severe twin to twin transfusion syn-drome after intrauterine laser coagulation. Heart2006;92:95-100. Level II-3.60. Shah AD, Border WL, Crombleholme TM,Michelfelder EC. Initial fetal cardiovascular pro-file score predicts recipient twin outcome intwin-twin transfusion syndrome. J Am SocEchocardiogr 2008;21:1105-8. Level II-2.61. Tei C. New non-invasive index for combinedsystolic and diastolic ventricular function. J Car-diol 1995;26:135-6. Level II-3.62. Papanna R, Mann LK, Molina S, Johnson A,Moise KJ. Changes in the recipient fetal Tei in-dex in the peri-operative period after laser pho-tocoagulation of placental anastomoses fortwin-twin transfusion syndrome. Prenat Diagn2011;31:176-80. Level II-2.63. Stirnemann JJ, Nasr B, Proulx F, EssaouiM, Ville Y. Evaluation of the CHOP cardiovascu-lar score as a prognostic predictor of outcomein twin-twin transfusion syndrome after lasercoagulation of placental vessels in a prospec-tive cohort. Ultrasound Obstet Gynecol 2010;36:52-7. Level II-2.64. Anderson BL, Sherman FS, Mancini F,Simhan HN. Fetal echocardiographic findingsare not predictive of death in twin-twin transfu-sion syndrome. J Ultrasound Med 2006;25:455-9. Level II-3.65. Senat MV, Deprest J, Boulvain M, Paupe A,
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The practice of medicine continues toevolve, and individual circumstances willvary. This opinion reflects information avail-able at the time of its submission for publi-cation and is neither designed nor intendedto establish an exclusive standard of peri-natal care. This publication is not expectedto reflect the opinions of all members of theSociety for Maternal-Fetal Medicine.

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