CLINICAL OBSTETRICS AND GYNECOLOGY Volume 58, Number 3, 611–631 Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved.
Diagnosis and Management of Twin-Twin Transfusion Syndrome ANTHONY JOHNSON, DO*w *Departments of Obstetrics, Gynecology and Reproductive Sciences, and Pediatric Surgery, University of Texas Health Science Center; and w The Fetal Center at Children’s Memorial Hermann Hospital, Houston, Texas Abstract: Twin-twin transfusion syndrome (TTTS) affects 10% to 15% of monochorionic pregnancies. In the absences of timely diagnosis and intervention perinatal loss or long term developmental delay can be expected in over 90% of cases. Establishing chorionicity in the first trimester followed by serial ultrasounds beginning at 16 weeks of gestation and intervention with placental laser ablation before the development of advance disease overall survival rates can be expected in 70% to 80% of cases. Key words: twin-twin transfusion syndrome, laser ablation, monochorionic
Correspondence: Anthony Johnson, DO, Departments of Obstetrics, Gynecology and Reproductive Sciences and Pediatric Surgery, University of Texas Health Science Center, 6410 Fannin, Suite 700, Houston, TX. E-mail: [email protected] A.J. receives royalty payments for authorship of the chapters on pathogenesis, diagnosis, and management of twin-twin transfusion syndrome in UpToDate. CLINICAL OBSTETRICS AND GYNECOLOGY
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Introduction Essentially all monochorionic (MC) twin pregnancies have some component of twin-twin transfusion due to the universal presence of intertwin placental vascular anastomoses. Fortunately, in the majority of these at-risk pregnancies distribution of the placental share and flow through the placental anastomoses are balanced thereby avoiding significant clinical consequences that are unique to MC pregnancies. Hemodynamic shifts, acute or chronic, through these vascular anastomoses are the key component to the 6-fold increase in perinatal mortality seen in MC when compared with dichorionic (DC) twins.1 Chronic twin-twin transfusion syndrome (TTTS) accounts for the majority of these losses. If TTTS develops before 26 weeks and is left untreated, perinatal mortality and/or long-term morbidity will be seen in over 90% cases. VOLUME 58
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TTTS is associated with perinatal mortality in 17% of all twin and over 40% of MC multifetal deaths despite the advance and access to improved fetal interventions.2 At the present time there are no means of preventing the development of TTTS. Improvement in perinatal outcome is dependent on early recognition of monochorionicity, aggressive fetal monitoring, and intervention when critical thresholds for TTTS are met. TTTS may occur as an acute manifestation in MC pregnancies after the in utero death of a co-twin, acute perimortem TTTS or on rare occasions intrapartum, acute perinatal TTTS. Discussion of the acute forms of TTTS is beyond the scope of this chapter. The objective of this chapter is to provide a concise review of the pathophysiology, diagnosis, management, and risk factors associated with perinatal and long-term infant outcome from pregnancies affected with chronic TTTS. Recommendations are based on well-designed studies that have been shown to be cost effective, clinically practical with proven benefit. In the absence of such studies, where evidence is suggested but unproven, the author’s recommendations are based on the consensus from expert opinions.
Incidence The true incidence of TTTS is unknown due to the high perinatal loss rate of undetected pregnancies in the second trimester. Various reports have suggested that 9% to 15% of MC twin pregnancies are affected with TTTS.3 Assuming 30% of twins are monozygotic of which 70% are MC and a twin birth rate of 33.7 per 1000 pregnancies, there will be around 2780 to 4170 twin pairs affected with TTTS annually.4
Pathophysiology Although early signs of chronic TTTS may be seen in the first trimester, the
clinical manifestations usually do not become apparent until the second and early third trimester. Chronic TTTS is a rare occurrence after 30 weeks of gestation. The initial clinical feature of TTTS are attributed to discordance in the intravascular volume between the twins with hypervolemia resulting in polyuria and polyhydramnios in one twin, the recipient, and hypovolemia, and secondary reduced renal perfusion resulting in oliguria and oligohydramnios in the co-twin, the donor. With disease, both the twins are at risk for in utero demise quite due to cardiac decompensation and eventual hydrops in the recipient and growth lag with hypoxic-ischemic injuries in the donor. Uterine overdistention from polyhydramnios can result in severe maternal discomfort, respiratory compromise, cervical change with preterm rupture of membranes, and/or labor. Understanding the pathophysiology that results in the clinical cascade of TTTS has been an academic challenge. The essential pathophysiological mechanisms are inaccessible in the human fetus and there are no suitable MC animal models to study TTTS. Therefore, computational models have been developed along with placental perfusion studies to gain insight into the essential components of fetal and placental pathophysiology that are implicated in the development and subsequent treatment of TTTS. Essentially all MC placentas have placenta vascular anastomoses. These communications may be arteriovenous (AVA), arterio-arterial (AAA), or veno-venous (VVV). AVAs are found in 95% of MC pregnancy. Flow is unidirectional with a feeding artery from one twin communicating at the capillary level in a common cotyledon below the placental surface with a draining vein from the other twin. AAA and VVA are found on the placental surface in 80% and 20% of MC pregnancies, respectively. Flow appears to be bidirectional in the surface vessels with net flow being
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Twin-Twin Transfusion Syndrome dependent on the hydrostatic pressures of fetuses. Placental angioarchitecture develops during embryogenesis and with advancing gestation and placental growth, there is disruption of the anastomoses in a random manner. The exact pathophysiological role that placental vascular anastomoses play in the development of TTTS is not entirely clear. Modeling has suggested that the hemodynamic status of the twins is clinically balanced when there are AVA going in both directions or in those cases where there is an excess of AVA in one direction, the imbalance in vascular flow is compensated for by AAA. A disproportion in the AVA:AAA ratio is felt to be a key component in the hemodynamic imbalance that ultimately results in TTTS.5 The placental perfusion studies provided support for the computer modeling of unbalanced flow between the twins in chronic TTTS. These studies have demonstrated a difference in the frequency of the type and size of vascular anastomoses when comparing TTTS pregnancies with controls. AAAs are seen less frequently in TTTS than unaffected pregnancies, 30% to 40% versus 80% to 90%.6,7 These observations have led to the suggestion that AAA may have a protective role in preventing the development of TTTS in MC placentas. Alternatively, VVA are found more frequently in TTTS affected than unaffected MC pregnancies. Zhao and colleagues studied placentas without AAA and found a significant difference in the frequency of VVA in TTTS versus non-TTTS placentas, 37% (11/30) versus 7% (3/41), respectively (P8 cm
TABLE 1. Diagnostic Criteria for TwinTwin Transfusion Syndrome Confirm monochorionic pregnancy Polyhydramnios in the recipient twin 16-20 wk MVP>8 cm 21-26 wk MVP>8 cm* Oligohydramnios in the donor, 8 cm; European Centers >10 cm. MVP indicates maximum vertical pocket.
and European centers use MVP>10 cm. In addition, the fetal bladders are discordant is size with the recipient twin having a persistently dilated bladder, whereas the donor twin has a small, noncycling, or nonvisualized bladder. Discordance in fetal growth will be seen in 20% to 50% of TTTS cases, but is not a criterion for the diagnosis of TTTS. Similarly, with advancing disease Doppler profile of the UA or umbilical vein (UV) or ductus venosus (DV) will become abnormal in either or both twins. As such Doppler studies are prognostic indicators of outcome but are not a part of the diagnostic criteria for TTTS. Discordance in placental echogenicity between the donor and recipient segments of the placenta has been suggested as an additional diagnostic criterion for TTTS.18 This observation has been seen in the absence of TTTS and as such would not be considered diagnostic for TTTS. However this is not an uncommon observation when there is secondary twin anemia polycythemia sequence (TAPS) with TOPS.19 TAPS, is an atypical form of chronic TTTS that presents as a large intertwin hemoglobin difference due to chronic intertwin blood transfusion through small AVAs resulting in an anemic donor and polycythemic recipient. In the majority of cases TAPS is felt to be a slow process that allows time for hemodynamic compensatory mechanisms to
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Twin-Twin Transfusion Syndrome occur avoiding the activation of the RAS and subsequent development to TOPS. However, when long standing early in gestation TAPS may progress to TOPS. Spontaneous TAPS is found in 3% to 5% of MC pregnancies. In TTTS cases with secondary TAPS the hyperechoic, thickened donor portion of the placenta will have reduced vascular Doppler signal, whereas the recipient portion is hypoechoic with a distinct boundary dividing the 2 segments (Fig. 1). The antenatal diagnosis of TAPS is based on discordant blood flow in the middle cerebral artery peak systolic velocities (MCA-PSV). The anemia donor has an elevated MCA-PSV> 1.5 multiples of the median (MOM) and the polycythemic recipient has a reduced MCA-PSV20% or >95th percentile Absent or reversed Doppler blood flow in the A-wave of the ductus venosus Discordant amniotic fluid volumes Second trimester Discordant in abdominal circumference Intertwin membrane folding Velamentous cord insertion Discordant amniotic fluid volume Absence of placental aterioarterial anastomoses Discordance in placental echogenicity, donor portion hyperechoic, and thickened
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It has been suggested that the discordance in NT measurements in MC pregnancies may be an early manifestation of the hypervolemia and cardiac decompensation in the recipient twin in early TTTS. Subsequently reports have confirmed that discordance or NT measurements >95th percentile in MC pregnancies eventually develop TTTS; however, similar to reports of discordance in CRL measurements there has been varying sensitivity and the observation was not specific to TTTS. Discordant NT measurements in MC twins have been associated with an increased risk of fetal aneuploidy, discordance growth without TTTS, and intrauterine fetal demise.23–27 Doppler blood flow studies of the DV have been considered surrogate of cardiac function. As such it has been suggested that the hemodynamic imbalance and the cardiac dysfunction of TTTS may be indirectly manifested early in gestation by abnormal blood flow in the DV. Abnormal flow, defined as absent or reversed flow in the A-wave of the DV at 11 to 13 weeks is seen twice as often in MC versus DC twin pregnancies. The eventual development of TTTS was found to occur more often when critically abnormal Doppler flow was present in the DV during the first trimester flow than when flow was normal, OR 5.09, 95% CI, 1.94-13.37, P = 0.01.28 Assuming that 15% of MC pregnancies will be affected with TTTS, the prevalence increased to 30% with abnormal Doppler flow in the DV and reduced to 10% when flow was normal. Further support for the use of DV Doppler blood flow studies for the detection of TTTS are found in a later report where abnormal Doppler DV, in conjunction with discordance in NT >0.6 mm, was reported to have a relative risk (RR) of developing TTTS of 21, [RR = 20.75; 95% CI, 5.45-98.33].29 These results suggest that Doppler blood flow studies of the DV may prove to be useful to modify risk of TTTS. If the early results are confirmed, Doppler DV could be a useful marker to regulate
monitoring of MC pregnancies in the future. However, it should be noted that 40% of MC twin pregnancies with abnormal DV flow at 11 to 13 weeks will have a normal perinatal outcome.28 Intertwin membrane folding is an early manifestation of discordance in AFV between the twins. The evolving polyuria and polyhydramnios in future recipient’s sac with oliguria and oligohydramnios in the future donor’s sac result in collapsing or folding of the donor sac upon itself. Intertwin membrane folding is reported to occur at 15 to 17 weeks in 25% to 30% of MC twin pregnancies with 40% to 50% of these pregnancies progressing to severe TTTS.24,30 The likelihood ratio of the eventual development of TTTS with membrane folding at 15 to 17 weeks was reported to be 4.2 (95% CI, 3.0-6.0).30 Although a potential marker was considered initially to modify imaging frequency, with the implementation of serial ultrasound evaluations, every 2 weeks, beginning at 16 weeks to screen MC pregnancies there have been no additional report on the use of membrane folding in detecting TTTS. Velamentous cord insertion (VCI), a known risk factor for placental insufficiency and fetal growth lag in MC twins, has been suggested to be a risk factor for the development of TTTS. In a consecutive series of 284 MC twin placentas submitted for gross and histopathologic evaluation, De Paepe et al31 found a higher incidence of VCI in TTTS versus nonTTTS MC placentas, 14/42 (33%) versus 41/394 (10%), P30).33 These reports have demonstrated that Doppler imaging of placental anastomoses is feasible but technical constraints with associated high failure rates need to be resolved before antenatal
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assessment of placental anastomoses by Doppler can be considered as a clinical tool in the management of TTTS. The proposed first-trimester markers may provide some insight into which MC pregnancy may be at risk for TTTS, but the absence of such factors does not preclude the development of TTTS. The signs and symptoms of TTTS with the development of TOPS are well defined. To determine the optimal time for surveillance Sueters and colleagues reported their findings from a small prospective study of 23 MC pregnancies where serial ultrasounds began at16 weeks of gestation and were performed at least every 2 weeks thereafter, or more often if the patient complained of rapid increase in abdominal girth or had premature contraction. Ultrasound parameters that were assessed included folding of intertwin membrane, Doppler of the UA and UV and DV, fetal biometry for estimated fetal weight, and MVP of each gestational sac. TTTS was diagnosed when TOPS developed using the European criteria for polyhydramnios after 20 weeks. Using this protocol all cases of TTTS were diagnosed before severe complications developed. The overall survival rate with intervention was 75%. MVP in the future recipient twin was the ultrasound predictor of TTTS. None of the other secondtrimester ultrasound parameters were found to be predictive of future TTTS.34 Similarly, Lewi et al21 found that when comparing fetal biometry (abdominal circumference, biparietal diameter, head circumference, and femur length), UA Doppler, umbilical cord placental insertion site, and MVPs at 16 weeks, discordant AFVs was the only parameter that was significant in predicting TTTS (P = 0.0002), with sensitivity of 67%, false-positive rate 10%, and positive predictive value 40%. In light of these findings, it is now recommended that after first trimester confirmation of placental chorionicity, www.clinicalobgyn.com
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11 to 14 weeks, ultrasound examination be performed in MC pregnancies at least every 2 weeks beginning 16 weeks of gestation for the detection of TTTS35 (Fig. 2). When there is discordant AFV, or other potential risk factors such as increased NT, discordant growth, or critically abnormal Doppler DV, it may be
advisable to increase surveillance to weekly due to the increased risk of various perinatal complications associated with MC pregnancies, including TTTS, fetal growth lag, and fetal demise. The rate of congenital anomalies in twins is twice that seen in singleton pregnancies. When compared with chorionicity and
11-14 weeks Confirm chorionicity and amnioicity Nuchal Translucency Measurements
16 weeks Serial ultrasound, alternating every 2 weeks Limited survey: Amniotic fluid assessment MVP in each sac, assess bladder size and presence in each fetus Growth ultrasound: fetal biometry, MVP in each sac, Doppler UA if discordance in EFW > 20%, Doppler MCA PSV for TAPs after 18 weeks
MVP > 2cm and < 8 cm Yes
MCA PSV > 1.0 and < 1.5 MOM No
MVP < 2cm in one sac and > 8 cm in other = TTTS MCA PSV < 1.0 in one and > 1.5 MOM in other = TAPS
Referral to Fetal Treatment Center for evaluation
FIGURE 2. Algorithm for screening for chronic forms of twin-twin transfusion syndrome. EFW indicates estimated fetal weight; MCA, middle cerebral artery; MOM, multiple of the median; MVP, maximum vertical pocket; PSV, peak systolic velocity; TAPS, twin anemia polycythemia sequence; TTTS, twin-twin transfusion syndrome; UA, umbilical artery.
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Twin-Twin Transfusion Syndrome excluding chromosomal abnormalities, MC pregnancies are found to have nearly twice as many malformations as what will be seen in DC twin pregnancies. In particular, the risk for structural heart disease is significantly higher in MC twins versus DC twin pregnancies, RR 6.5 (95% CI, 4.23-10.01) and with TTTS there is further increase with RR 15.04 (95% CI, 9.78-23.13).36 Therefore screening of MC twin pregnancies should include a comprehensive anatomic survey with fetal echocardiography.
Staging The Quintero staging for TTTS is generally accepted as the staging method for TTTS at this time37 (Table 3). The 5 stages of disease are based on the findings from 2-dimensional ultrasound and Doppler blood flow studies of the UA, UV, and DV. MCA-PSV is not a part of the Quintero staging of TTTS. Quintero staging has been called into questions due to a number of limitations. Atypical presentations can occur, where the donor has reduced amniotic fluid with bladder seen but has abnormal UA Doppler. Higher Quintero stages are generally not associated with a worse perinatal outcome if there is an appropriate intervention, TABLE 3.
Staging of Twin-Twin Transfusion Syndrome36
Stage I: Oligohydramnios and polyhydramnios Stage II: Oligohydramnios and polyhydramnios; fetal bladder of donor is not visualized Stage III: Oligohydramnios and polyhydramnios with abnormal Doppler blood flow studies in either or both twins* Umbilical artery: absent or reversed diastolic flow Ductus venosus: absent or reversed flow of the awave or Umbilical vein: pulsatile flow Stage IV: One or both of the twins with fetal hydrops Stage V: Death of one or both twins *All Doppler measurements are critical to fully evaluate and complete staging.
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placental laser ablation. The clinical presentation of a particular case does not always follow an orderly progression from stage to stage. There can be a rapid progression from stage I to stage IV-V TTTS in upwards of 5% of case without any intermediate worsening stage.38 The rapid progression in stage I may be due to underlying cardiac compromise in the recipient twin that goes undetected in the Quintero staging. Over 60% of stage I recipients have been found to have early signs of cardiac decompensation in the recipient twin due to ventricular hypertrophy, AV valve regurgitation, or quantitative abnormalities of the ventricular function.39 Stage III is defined by abnormal Doppler blood flow in the UA, UV, or DV in the donor and/or recipient, but the pathologic processes that result in these abnormal studies are generally quite different. Abnormal UA Doppler in the donor is typically a factor of placental insufficiency. Abnormal DV and UV Doppler in the recipient is more than not representative of hypervolemia and cardiac decompensation. It has been suggested that a more comprehensive staging system is needed for TTTS. One who incorporates quantitative assessments of fetal urinary output, redefines polyhydramnios with advancing gestation, and incorporates ultrasound indices of myocardial function. While recognizing these limitations in the Quintero staging Stamilio et al,40 in their consensus panel reported that there are insufficient data to recommend revising or abandoning the use of the Quintero staging system for TTTS. The panel acknowledged that there are other potential physiological parameters that appear promising for the detection of TTTS, but before implementation as standard of care these candidate predictive indices need to be compared and validated in prospective cohort studies. These studies are ongoing at referral centers and as such are not ready for implementation in the screening paradigm. www.clinicalobgyn.com
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Treatment With expectant observation of TTTS that develops before 26 weeks of gestation intact dual survival can be expected in approximately 10% of cases. Serial amnioreduction (AR) and AR with microseptostomy are palliative treatments for TTTS. Removing the excess amniotic fluid in the gestational sac of the recipient twin reduces uterine distention, a risk factor preterm labor, prelabor premature rupture of membranes (PPROM), advanced cervical change and improves maternal discomfort. Reduction in AFV has potential fetal benefits as well. AR decreases the intra-amniotic pressure, which in turn may improve uteroplacental perfusion. Severe TTTS before 26 weeks treated with AR is reported to have survival rates of at least 1 twin in 50% to 60% with long-term neurological compromise seen in 25% to 30% of survivors.41–43 The clinical threshold for AR is subjective. In those patients who are found to have severe polyhydramnios uterine overdistention before 26 weeks of gestation resulting in respiratory compromise, frequent uterine contraction, or advanced cervical change and are remote from a fetal treatment center where placental laser ablation is available, AR may decrease the risk of preterm delivery and allow stabilization for transfer. AR is most probably useful in prolonging pregnancy when there is mild TTTS, stage I or II after 26 weeks of gestation in the United States since the Food and Drug Administration has only approved the use of fetoscopes for treatment of TTTS from 16 to 26 weeks. For AR to be effective there must be a sufficient amount of fluid removed to normalize the AFV in the recipient sac; however, rapid decompression or removal of more than 5 liters in a single setting will increase the risk of placenta abruption and or fetal bradycardia. AR with microseptostomy along with reducing the AFV in the recipient twin’s gestational sac there is a secondary goal to equilibrate the intra-amniotic pressures and AFVs between the donor and
recipient sacs. In AR alone, the aspirating needle is inserted under ultrasound guidance with the intention to only traverse the amnion of the recipient twin’s sac. With microseptostomy the needle is directed through both the donor and the recipient amnions. Microseptostomy may be performed alone, but is usually performed with AR of the recipient sac through a single puncture. Multiple punctures in the dividing membrane have been associated with intertwin membrane disruption resulting in cord entanglement, monoamnionicity, and fetal demise. A randomized trial comparing AR to AR with microseptostomy in the treatment of TTTS before 24 weeks found no difference in the survival rates but demonstrate a reduction in the number of procedures in the microseptostomy group (46% vs. 69%, P = 0.04).44 Like AR alone, microseptostomy should be limited to mild forms of TTTS after 26 weeks. Both the procedures have been associated with complications that may preclude successful definitive treatment with placental laser ablation. These complications include iatrogenic membrane separation (9%), septostomy preventing future membrane puncture (10% to 25%), and discolored or bloody amniotic fluid (>25%). Selective feticide may be the best option when TTTS is complicated with lifethreatening malformation in 1 fetus, there is severe fetal growth restriction remote from viability, recurrent TTTS, severe TAPS, failed laser due to proximate placental cord insertions or significant intraamniotic bleeding or markedly discolored fluid from previous intrauterine procedure or iatrogenic subchorionic hematoma and bleeding. Some have advocated stage IV TTTS to proceed with selective feticide; however, there have been numerous reports that have demonstrated survival rates of over 50% after placental laser ablation in advanced stages of TTTS where there is severe cardiac decompensation and fetal hydrops in the recipient
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Twin-Twin Transfusion Syndrome twin. Experience with selective feticide in TTTS is limited, with survival rate of 1 twin 77% to 92% and PPROM 20% within 3 weeks of the bipolar cord coagulation (BPC).45–47 In a more recent report comparing BPC to radiofrequency ablation (RFA) for selective reduction in complicated MC pregnancies, including TTTS, found no difference in the overall survival rates with 87.5% in the RFA group and 88% in the BPC group (P = 0.94); median gestational age at delivery was 36 weeks (range, 26 to 41 wk) in the RFA group and 39 weeks (range, 19 to 40 wk) in the BPC group (P = 0.59). However, the PPROM rate was higher in the BPC group (22.5%) compared with the RFA group (5%), the difference was not statistically significant (P = 0.09).48 Placental laser ablation is the treatment of choice for the TTTS between 16 and 26 weeks. The procedure was validated in Eurofetus randomized controlled trial comparing serial AR with selective laser ablation in the treatment of 142 cases of severe TTTS between 16 and 26 weeks.43 The laser group delivered later compared with the AR group, 33.3 versus 29.0 weeks (P = 0.004); had significantly higher rate of at least one twin surviving at 6 months (76% vs. 56%, P = 0.009); a lower incidence of periventricular leukomalacia (6% vs. 14%); and survivors were more likely to be free of neurological complications at 6 months of age (52% vs. 31%, P = 0.003). From the original trial, 128 (90%) cases were recruited and randomized in France. In a subsequent study of the long-term follow-up from the survivors from the French cohort, 120 children were followed to 6 years of age, 73 laser, and 47 AR survivors. The difference in neurological outcome between the groups was no longer seen at 6 years of age with normal development seen in 60/73 (82%) of laser survivors and 33/47 (70%) AR survivors.49 In the meta-analysis by Rossi and D’Addario comparing laser and serial
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AR for treatment of severe TTTS in 1006 cases laser fetuses undergoing laser ablation were twice as likely to survive and had an 80% reduction in neurological morbidity (overall survival OR 2.04, 95% CI, 1.52-2.76; neonatal death OR 0.24, 95% CI, 0.15-0.40; neurological morbidity OR 0.20, 95% CI, 0.12-0.33).42 In 2014 Cochrane Database review of the 2 randomized trials comparing laser and AR in 182 pregnancies there was no difference in overall death, death of one or both twins. These outcomes were different across the 2 trials. There were more babies alive without neurological abnormality at 6 years in the laser group than in the AR group (RR 1.57; 95% CI, 1.052.34). The authors concluded that endoscopic laser of anastomotic vessels should continue to be considered the treatment of all stages of TTTS to improve neurodevelopmental outcomes; however, further research is needed to determine the effect of treatment of milder (stage I) and more severe (stage IV) forms of TTTS. Studies should aim to assess the long-term outcomes of survivors.50 Laser ablation is usually undertaken for Quintero stages II to IV between 16 and 26 weeks of gestation. In the United States, FDA approved the TTTS fetoscopes instruments set under the Humanitarian Device Exemption (HDE) program exemption, H040005, for the treatment of TTTS for this time period only (http://www.accessdata.fda.gov/cdrh_docs/pdf4/h040005a.pdf). There is, however, increasing evidence that laser ablation above and below these arbitrary cutoffs have comparable outcomes in survival rates and complication rates.51–54 Data are limited on the impact of intervention for stage I TTTS. In the Eurofetus Trial, there were only 11 stage I cases, 6 laser and 5 AR cases and they were analyzed together with the stage II cases.43 Comparing outcomes from stage I cases that have undergone laser photocoagulation or observation with or without AR survival rates have been comparable www.clinicalobgyn.com
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with dual survival and at least one twin survivor (ALOS) were 71% to 90% and 91% to 100% in the laser groups and 70% to 77% and 92% to 97% in the expectant observation group.55–59 In an international survey of over 80 fetal treatment centers, when asked how they would manage uncomplicated stage I TTT, expectant management was the predominant recommendation (78%), followed by AR (11%), laser ablation (11%), and septostomy (1%).60 When examples of special patient circumstances were presented, either severe uterine overdistention with maternal discomfort and MVP 14 cm or there was advanced cervical change with cervical length of
Diagnosis and Management of Twin-Twin Transfusion Syndrome ANTHONY JOHNSON, DO*w *Departments of Obstetrics, Gynecology and Reproductive Sciences, and Pediatric Surgery, University of Texas Health Science Center; and w The Fetal Center at Children’s Memorial Hermann Hospital, Houston, Texas Abstract: Twin-twin transfusion syndrome (TTTS) affects 10% to 15% of monochorionic pregnancies. In the absences of timely diagnosis and intervention perinatal loss or long term developmental delay can be expected in over 90% of cases. Establishing chorionicity in the first trimester followed by serial ultrasounds beginning at 16 weeks of gestation and intervention with placental laser ablation before the development of advance disease overall survival rates can be expected in 70% to 80% of cases. Key words: twin-twin transfusion syndrome, laser ablation, monochorionic
Correspondence: Anthony Johnson, DO, Departments of Obstetrics, Gynecology and Reproductive Sciences and Pediatric Surgery, University of Texas Health Science Center, 6410 Fannin, Suite 700, Houston, TX. E-mail: [email protected] A.J. receives royalty payments for authorship of the chapters on pathogenesis, diagnosis, and management of twin-twin transfusion syndrome in UpToDate. CLINICAL OBSTETRICS AND GYNECOLOGY
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Introduction Essentially all monochorionic (MC) twin pregnancies have some component of twin-twin transfusion due to the universal presence of intertwin placental vascular anastomoses. Fortunately, in the majority of these at-risk pregnancies distribution of the placental share and flow through the placental anastomoses are balanced thereby avoiding significant clinical consequences that are unique to MC pregnancies. Hemodynamic shifts, acute or chronic, through these vascular anastomoses are the key component to the 6-fold increase in perinatal mortality seen in MC when compared with dichorionic (DC) twins.1 Chronic twin-twin transfusion syndrome (TTTS) accounts for the majority of these losses. If TTTS develops before 26 weeks and is left untreated, perinatal mortality and/or long-term morbidity will be seen in over 90% cases. VOLUME 58
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Johnson
TTTS is associated with perinatal mortality in 17% of all twin and over 40% of MC multifetal deaths despite the advance and access to improved fetal interventions.2 At the present time there are no means of preventing the development of TTTS. Improvement in perinatal outcome is dependent on early recognition of monochorionicity, aggressive fetal monitoring, and intervention when critical thresholds for TTTS are met. TTTS may occur as an acute manifestation in MC pregnancies after the in utero death of a co-twin, acute perimortem TTTS or on rare occasions intrapartum, acute perinatal TTTS. Discussion of the acute forms of TTTS is beyond the scope of this chapter. The objective of this chapter is to provide a concise review of the pathophysiology, diagnosis, management, and risk factors associated with perinatal and long-term infant outcome from pregnancies affected with chronic TTTS. Recommendations are based on well-designed studies that have been shown to be cost effective, clinically practical with proven benefit. In the absence of such studies, where evidence is suggested but unproven, the author’s recommendations are based on the consensus from expert opinions.
Incidence The true incidence of TTTS is unknown due to the high perinatal loss rate of undetected pregnancies in the second trimester. Various reports have suggested that 9% to 15% of MC twin pregnancies are affected with TTTS.3 Assuming 30% of twins are monozygotic of which 70% are MC and a twin birth rate of 33.7 per 1000 pregnancies, there will be around 2780 to 4170 twin pairs affected with TTTS annually.4
Pathophysiology Although early signs of chronic TTTS may be seen in the first trimester, the
clinical manifestations usually do not become apparent until the second and early third trimester. Chronic TTTS is a rare occurrence after 30 weeks of gestation. The initial clinical feature of TTTS are attributed to discordance in the intravascular volume between the twins with hypervolemia resulting in polyuria and polyhydramnios in one twin, the recipient, and hypovolemia, and secondary reduced renal perfusion resulting in oliguria and oligohydramnios in the co-twin, the donor. With disease, both the twins are at risk for in utero demise quite due to cardiac decompensation and eventual hydrops in the recipient and growth lag with hypoxic-ischemic injuries in the donor. Uterine overdistention from polyhydramnios can result in severe maternal discomfort, respiratory compromise, cervical change with preterm rupture of membranes, and/or labor. Understanding the pathophysiology that results in the clinical cascade of TTTS has been an academic challenge. The essential pathophysiological mechanisms are inaccessible in the human fetus and there are no suitable MC animal models to study TTTS. Therefore, computational models have been developed along with placental perfusion studies to gain insight into the essential components of fetal and placental pathophysiology that are implicated in the development and subsequent treatment of TTTS. Essentially all MC placentas have placenta vascular anastomoses. These communications may be arteriovenous (AVA), arterio-arterial (AAA), or veno-venous (VVV). AVAs are found in 95% of MC pregnancy. Flow is unidirectional with a feeding artery from one twin communicating at the capillary level in a common cotyledon below the placental surface with a draining vein from the other twin. AAA and VVA are found on the placental surface in 80% and 20% of MC pregnancies, respectively. Flow appears to be bidirectional in the surface vessels with net flow being
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Twin-Twin Transfusion Syndrome dependent on the hydrostatic pressures of fetuses. Placental angioarchitecture develops during embryogenesis and with advancing gestation and placental growth, there is disruption of the anastomoses in a random manner. The exact pathophysiological role that placental vascular anastomoses play in the development of TTTS is not entirely clear. Modeling has suggested that the hemodynamic status of the twins is clinically balanced when there are AVA going in both directions or in those cases where there is an excess of AVA in one direction, the imbalance in vascular flow is compensated for by AAA. A disproportion in the AVA:AAA ratio is felt to be a key component in the hemodynamic imbalance that ultimately results in TTTS.5 The placental perfusion studies provided support for the computer modeling of unbalanced flow between the twins in chronic TTTS. These studies have demonstrated a difference in the frequency of the type and size of vascular anastomoses when comparing TTTS pregnancies with controls. AAAs are seen less frequently in TTTS than unaffected pregnancies, 30% to 40% versus 80% to 90%.6,7 These observations have led to the suggestion that AAA may have a protective role in preventing the development of TTTS in MC placentas. Alternatively, VVA are found more frequently in TTTS affected than unaffected MC pregnancies. Zhao and colleagues studied placentas without AAA and found a significant difference in the frequency of VVA in TTTS versus non-TTTS placentas, 37% (11/30) versus 7% (3/41), respectively (P8 cm
TABLE 1. Diagnostic Criteria for TwinTwin Transfusion Syndrome Confirm monochorionic pregnancy Polyhydramnios in the recipient twin 16-20 wk MVP>8 cm 21-26 wk MVP>8 cm* Oligohydramnios in the donor, 8 cm; European Centers >10 cm. MVP indicates maximum vertical pocket.
and European centers use MVP>10 cm. In addition, the fetal bladders are discordant is size with the recipient twin having a persistently dilated bladder, whereas the donor twin has a small, noncycling, or nonvisualized bladder. Discordance in fetal growth will be seen in 20% to 50% of TTTS cases, but is not a criterion for the diagnosis of TTTS. Similarly, with advancing disease Doppler profile of the UA or umbilical vein (UV) or ductus venosus (DV) will become abnormal in either or both twins. As such Doppler studies are prognostic indicators of outcome but are not a part of the diagnostic criteria for TTTS. Discordance in placental echogenicity between the donor and recipient segments of the placenta has been suggested as an additional diagnostic criterion for TTTS.18 This observation has been seen in the absence of TTTS and as such would not be considered diagnostic for TTTS. However this is not an uncommon observation when there is secondary twin anemia polycythemia sequence (TAPS) with TOPS.19 TAPS, is an atypical form of chronic TTTS that presents as a large intertwin hemoglobin difference due to chronic intertwin blood transfusion through small AVAs resulting in an anemic donor and polycythemic recipient. In the majority of cases TAPS is felt to be a slow process that allows time for hemodynamic compensatory mechanisms to
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Twin-Twin Transfusion Syndrome occur avoiding the activation of the RAS and subsequent development to TOPS. However, when long standing early in gestation TAPS may progress to TOPS. Spontaneous TAPS is found in 3% to 5% of MC pregnancies. In TTTS cases with secondary TAPS the hyperechoic, thickened donor portion of the placenta will have reduced vascular Doppler signal, whereas the recipient portion is hypoechoic with a distinct boundary dividing the 2 segments (Fig. 1). The antenatal diagnosis of TAPS is based on discordant blood flow in the middle cerebral artery peak systolic velocities (MCA-PSV). The anemia donor has an elevated MCA-PSV> 1.5 multiples of the median (MOM) and the polycythemic recipient has a reduced MCA-PSV20% or >95th percentile Absent or reversed Doppler blood flow in the A-wave of the ductus venosus Discordant amniotic fluid volumes Second trimester Discordant in abdominal circumference Intertwin membrane folding Velamentous cord insertion Discordant amniotic fluid volume Absence of placental aterioarterial anastomoses Discordance in placental echogenicity, donor portion hyperechoic, and thickened
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It has been suggested that the discordance in NT measurements in MC pregnancies may be an early manifestation of the hypervolemia and cardiac decompensation in the recipient twin in early TTTS. Subsequently reports have confirmed that discordance or NT measurements >95th percentile in MC pregnancies eventually develop TTTS; however, similar to reports of discordance in CRL measurements there has been varying sensitivity and the observation was not specific to TTTS. Discordant NT measurements in MC twins have been associated with an increased risk of fetal aneuploidy, discordance growth without TTTS, and intrauterine fetal demise.23–27 Doppler blood flow studies of the DV have been considered surrogate of cardiac function. As such it has been suggested that the hemodynamic imbalance and the cardiac dysfunction of TTTS may be indirectly manifested early in gestation by abnormal blood flow in the DV. Abnormal flow, defined as absent or reversed flow in the A-wave of the DV at 11 to 13 weeks is seen twice as often in MC versus DC twin pregnancies. The eventual development of TTTS was found to occur more often when critically abnormal Doppler flow was present in the DV during the first trimester flow than when flow was normal, OR 5.09, 95% CI, 1.94-13.37, P = 0.01.28 Assuming that 15% of MC pregnancies will be affected with TTTS, the prevalence increased to 30% with abnormal Doppler flow in the DV and reduced to 10% when flow was normal. Further support for the use of DV Doppler blood flow studies for the detection of TTTS are found in a later report where abnormal Doppler DV, in conjunction with discordance in NT >0.6 mm, was reported to have a relative risk (RR) of developing TTTS of 21, [RR = 20.75; 95% CI, 5.45-98.33].29 These results suggest that Doppler blood flow studies of the DV may prove to be useful to modify risk of TTTS. If the early results are confirmed, Doppler DV could be a useful marker to regulate
monitoring of MC pregnancies in the future. However, it should be noted that 40% of MC twin pregnancies with abnormal DV flow at 11 to 13 weeks will have a normal perinatal outcome.28 Intertwin membrane folding is an early manifestation of discordance in AFV between the twins. The evolving polyuria and polyhydramnios in future recipient’s sac with oliguria and oligohydramnios in the future donor’s sac result in collapsing or folding of the donor sac upon itself. Intertwin membrane folding is reported to occur at 15 to 17 weeks in 25% to 30% of MC twin pregnancies with 40% to 50% of these pregnancies progressing to severe TTTS.24,30 The likelihood ratio of the eventual development of TTTS with membrane folding at 15 to 17 weeks was reported to be 4.2 (95% CI, 3.0-6.0).30 Although a potential marker was considered initially to modify imaging frequency, with the implementation of serial ultrasound evaluations, every 2 weeks, beginning at 16 weeks to screen MC pregnancies there have been no additional report on the use of membrane folding in detecting TTTS. Velamentous cord insertion (VCI), a known risk factor for placental insufficiency and fetal growth lag in MC twins, has been suggested to be a risk factor for the development of TTTS. In a consecutive series of 284 MC twin placentas submitted for gross and histopathologic evaluation, De Paepe et al31 found a higher incidence of VCI in TTTS versus nonTTTS MC placentas, 14/42 (33%) versus 41/394 (10%), P30).33 These reports have demonstrated that Doppler imaging of placental anastomoses is feasible but technical constraints with associated high failure rates need to be resolved before antenatal
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assessment of placental anastomoses by Doppler can be considered as a clinical tool in the management of TTTS. The proposed first-trimester markers may provide some insight into which MC pregnancy may be at risk for TTTS, but the absence of such factors does not preclude the development of TTTS. The signs and symptoms of TTTS with the development of TOPS are well defined. To determine the optimal time for surveillance Sueters and colleagues reported their findings from a small prospective study of 23 MC pregnancies where serial ultrasounds began at16 weeks of gestation and were performed at least every 2 weeks thereafter, or more often if the patient complained of rapid increase in abdominal girth or had premature contraction. Ultrasound parameters that were assessed included folding of intertwin membrane, Doppler of the UA and UV and DV, fetal biometry for estimated fetal weight, and MVP of each gestational sac. TTTS was diagnosed when TOPS developed using the European criteria for polyhydramnios after 20 weeks. Using this protocol all cases of TTTS were diagnosed before severe complications developed. The overall survival rate with intervention was 75%. MVP in the future recipient twin was the ultrasound predictor of TTTS. None of the other secondtrimester ultrasound parameters were found to be predictive of future TTTS.34 Similarly, Lewi et al21 found that when comparing fetal biometry (abdominal circumference, biparietal diameter, head circumference, and femur length), UA Doppler, umbilical cord placental insertion site, and MVPs at 16 weeks, discordant AFVs was the only parameter that was significant in predicting TTTS (P = 0.0002), with sensitivity of 67%, false-positive rate 10%, and positive predictive value 40%. In light of these findings, it is now recommended that after first trimester confirmation of placental chorionicity, www.clinicalobgyn.com
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11 to 14 weeks, ultrasound examination be performed in MC pregnancies at least every 2 weeks beginning 16 weeks of gestation for the detection of TTTS35 (Fig. 2). When there is discordant AFV, or other potential risk factors such as increased NT, discordant growth, or critically abnormal Doppler DV, it may be
advisable to increase surveillance to weekly due to the increased risk of various perinatal complications associated with MC pregnancies, including TTTS, fetal growth lag, and fetal demise. The rate of congenital anomalies in twins is twice that seen in singleton pregnancies. When compared with chorionicity and
11-14 weeks Confirm chorionicity and amnioicity Nuchal Translucency Measurements
16 weeks Serial ultrasound, alternating every 2 weeks Limited survey: Amniotic fluid assessment MVP in each sac, assess bladder size and presence in each fetus Growth ultrasound: fetal biometry, MVP in each sac, Doppler UA if discordance in EFW > 20%, Doppler MCA PSV for TAPs after 18 weeks
MVP > 2cm and < 8 cm Yes
MCA PSV > 1.0 and < 1.5 MOM No
MVP < 2cm in one sac and > 8 cm in other = TTTS MCA PSV < 1.0 in one and > 1.5 MOM in other = TAPS
Referral to Fetal Treatment Center for evaluation
FIGURE 2. Algorithm for screening for chronic forms of twin-twin transfusion syndrome. EFW indicates estimated fetal weight; MCA, middle cerebral artery; MOM, multiple of the median; MVP, maximum vertical pocket; PSV, peak systolic velocity; TAPS, twin anemia polycythemia sequence; TTTS, twin-twin transfusion syndrome; UA, umbilical artery.
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Twin-Twin Transfusion Syndrome excluding chromosomal abnormalities, MC pregnancies are found to have nearly twice as many malformations as what will be seen in DC twin pregnancies. In particular, the risk for structural heart disease is significantly higher in MC twins versus DC twin pregnancies, RR 6.5 (95% CI, 4.23-10.01) and with TTTS there is further increase with RR 15.04 (95% CI, 9.78-23.13).36 Therefore screening of MC twin pregnancies should include a comprehensive anatomic survey with fetal echocardiography.
Staging The Quintero staging for TTTS is generally accepted as the staging method for TTTS at this time37 (Table 3). The 5 stages of disease are based on the findings from 2-dimensional ultrasound and Doppler blood flow studies of the UA, UV, and DV. MCA-PSV is not a part of the Quintero staging of TTTS. Quintero staging has been called into questions due to a number of limitations. Atypical presentations can occur, where the donor has reduced amniotic fluid with bladder seen but has abnormal UA Doppler. Higher Quintero stages are generally not associated with a worse perinatal outcome if there is an appropriate intervention, TABLE 3.
Staging of Twin-Twin Transfusion Syndrome36
Stage I: Oligohydramnios and polyhydramnios Stage II: Oligohydramnios and polyhydramnios; fetal bladder of donor is not visualized Stage III: Oligohydramnios and polyhydramnios with abnormal Doppler blood flow studies in either or both twins* Umbilical artery: absent or reversed diastolic flow Ductus venosus: absent or reversed flow of the awave or Umbilical vein: pulsatile flow Stage IV: One or both of the twins with fetal hydrops Stage V: Death of one or both twins *All Doppler measurements are critical to fully evaluate and complete staging.
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placental laser ablation. The clinical presentation of a particular case does not always follow an orderly progression from stage to stage. There can be a rapid progression from stage I to stage IV-V TTTS in upwards of 5% of case without any intermediate worsening stage.38 The rapid progression in stage I may be due to underlying cardiac compromise in the recipient twin that goes undetected in the Quintero staging. Over 60% of stage I recipients have been found to have early signs of cardiac decompensation in the recipient twin due to ventricular hypertrophy, AV valve regurgitation, or quantitative abnormalities of the ventricular function.39 Stage III is defined by abnormal Doppler blood flow in the UA, UV, or DV in the donor and/or recipient, but the pathologic processes that result in these abnormal studies are generally quite different. Abnormal UA Doppler in the donor is typically a factor of placental insufficiency. Abnormal DV and UV Doppler in the recipient is more than not representative of hypervolemia and cardiac decompensation. It has been suggested that a more comprehensive staging system is needed for TTTS. One who incorporates quantitative assessments of fetal urinary output, redefines polyhydramnios with advancing gestation, and incorporates ultrasound indices of myocardial function. While recognizing these limitations in the Quintero staging Stamilio et al,40 in their consensus panel reported that there are insufficient data to recommend revising or abandoning the use of the Quintero staging system for TTTS. The panel acknowledged that there are other potential physiological parameters that appear promising for the detection of TTTS, but before implementation as standard of care these candidate predictive indices need to be compared and validated in prospective cohort studies. These studies are ongoing at referral centers and as such are not ready for implementation in the screening paradigm. www.clinicalobgyn.com
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Treatment With expectant observation of TTTS that develops before 26 weeks of gestation intact dual survival can be expected in approximately 10% of cases. Serial amnioreduction (AR) and AR with microseptostomy are palliative treatments for TTTS. Removing the excess amniotic fluid in the gestational sac of the recipient twin reduces uterine distention, a risk factor preterm labor, prelabor premature rupture of membranes (PPROM), advanced cervical change and improves maternal discomfort. Reduction in AFV has potential fetal benefits as well. AR decreases the intra-amniotic pressure, which in turn may improve uteroplacental perfusion. Severe TTTS before 26 weeks treated with AR is reported to have survival rates of at least 1 twin in 50% to 60% with long-term neurological compromise seen in 25% to 30% of survivors.41–43 The clinical threshold for AR is subjective. In those patients who are found to have severe polyhydramnios uterine overdistention before 26 weeks of gestation resulting in respiratory compromise, frequent uterine contraction, or advanced cervical change and are remote from a fetal treatment center where placental laser ablation is available, AR may decrease the risk of preterm delivery and allow stabilization for transfer. AR is most probably useful in prolonging pregnancy when there is mild TTTS, stage I or II after 26 weeks of gestation in the United States since the Food and Drug Administration has only approved the use of fetoscopes for treatment of TTTS from 16 to 26 weeks. For AR to be effective there must be a sufficient amount of fluid removed to normalize the AFV in the recipient sac; however, rapid decompression or removal of more than 5 liters in a single setting will increase the risk of placenta abruption and or fetal bradycardia. AR with microseptostomy along with reducing the AFV in the recipient twin’s gestational sac there is a secondary goal to equilibrate the intra-amniotic pressures and AFVs between the donor and
recipient sacs. In AR alone, the aspirating needle is inserted under ultrasound guidance with the intention to only traverse the amnion of the recipient twin’s sac. With microseptostomy the needle is directed through both the donor and the recipient amnions. Microseptostomy may be performed alone, but is usually performed with AR of the recipient sac through a single puncture. Multiple punctures in the dividing membrane have been associated with intertwin membrane disruption resulting in cord entanglement, monoamnionicity, and fetal demise. A randomized trial comparing AR to AR with microseptostomy in the treatment of TTTS before 24 weeks found no difference in the survival rates but demonstrate a reduction in the number of procedures in the microseptostomy group (46% vs. 69%, P = 0.04).44 Like AR alone, microseptostomy should be limited to mild forms of TTTS after 26 weeks. Both the procedures have been associated with complications that may preclude successful definitive treatment with placental laser ablation. These complications include iatrogenic membrane separation (9%), septostomy preventing future membrane puncture (10% to 25%), and discolored or bloody amniotic fluid (>25%). Selective feticide may be the best option when TTTS is complicated with lifethreatening malformation in 1 fetus, there is severe fetal growth restriction remote from viability, recurrent TTTS, severe TAPS, failed laser due to proximate placental cord insertions or significant intraamniotic bleeding or markedly discolored fluid from previous intrauterine procedure or iatrogenic subchorionic hematoma and bleeding. Some have advocated stage IV TTTS to proceed with selective feticide; however, there have been numerous reports that have demonstrated survival rates of over 50% after placental laser ablation in advanced stages of TTTS where there is severe cardiac decompensation and fetal hydrops in the recipient
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Twin-Twin Transfusion Syndrome twin. Experience with selective feticide in TTTS is limited, with survival rate of 1 twin 77% to 92% and PPROM 20% within 3 weeks of the bipolar cord coagulation (BPC).45–47 In a more recent report comparing BPC to radiofrequency ablation (RFA) for selective reduction in complicated MC pregnancies, including TTTS, found no difference in the overall survival rates with 87.5% in the RFA group and 88% in the BPC group (P = 0.94); median gestational age at delivery was 36 weeks (range, 26 to 41 wk) in the RFA group and 39 weeks (range, 19 to 40 wk) in the BPC group (P = 0.59). However, the PPROM rate was higher in the BPC group (22.5%) compared with the RFA group (5%), the difference was not statistically significant (P = 0.09).48 Placental laser ablation is the treatment of choice for the TTTS between 16 and 26 weeks. The procedure was validated in Eurofetus randomized controlled trial comparing serial AR with selective laser ablation in the treatment of 142 cases of severe TTTS between 16 and 26 weeks.43 The laser group delivered later compared with the AR group, 33.3 versus 29.0 weeks (P = 0.004); had significantly higher rate of at least one twin surviving at 6 months (76% vs. 56%, P = 0.009); a lower incidence of periventricular leukomalacia (6% vs. 14%); and survivors were more likely to be free of neurological complications at 6 months of age (52% vs. 31%, P = 0.003). From the original trial, 128 (90%) cases were recruited and randomized in France. In a subsequent study of the long-term follow-up from the survivors from the French cohort, 120 children were followed to 6 years of age, 73 laser, and 47 AR survivors. The difference in neurological outcome between the groups was no longer seen at 6 years of age with normal development seen in 60/73 (82%) of laser survivors and 33/47 (70%) AR survivors.49 In the meta-analysis by Rossi and D’Addario comparing laser and serial
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AR for treatment of severe TTTS in 1006 cases laser fetuses undergoing laser ablation were twice as likely to survive and had an 80% reduction in neurological morbidity (overall survival OR 2.04, 95% CI, 1.52-2.76; neonatal death OR 0.24, 95% CI, 0.15-0.40; neurological morbidity OR 0.20, 95% CI, 0.12-0.33).42 In 2014 Cochrane Database review of the 2 randomized trials comparing laser and AR in 182 pregnancies there was no difference in overall death, death of one or both twins. These outcomes were different across the 2 trials. There were more babies alive without neurological abnormality at 6 years in the laser group than in the AR group (RR 1.57; 95% CI, 1.052.34). The authors concluded that endoscopic laser of anastomotic vessels should continue to be considered the treatment of all stages of TTTS to improve neurodevelopmental outcomes; however, further research is needed to determine the effect of treatment of milder (stage I) and more severe (stage IV) forms of TTTS. Studies should aim to assess the long-term outcomes of survivors.50 Laser ablation is usually undertaken for Quintero stages II to IV between 16 and 26 weeks of gestation. In the United States, FDA approved the TTTS fetoscopes instruments set under the Humanitarian Device Exemption (HDE) program exemption, H040005, for the treatment of TTTS for this time period only (http://www.accessdata.fda.gov/cdrh_docs/pdf4/h040005a.pdf). There is, however, increasing evidence that laser ablation above and below these arbitrary cutoffs have comparable outcomes in survival rates and complication rates.51–54 Data are limited on the impact of intervention for stage I TTTS. In the Eurofetus Trial, there were only 11 stage I cases, 6 laser and 5 AR cases and they were analyzed together with the stage II cases.43 Comparing outcomes from stage I cases that have undergone laser photocoagulation or observation with or without AR survival rates have been comparable www.clinicalobgyn.com
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with dual survival and at least one twin survivor (ALOS) were 71% to 90% and 91% to 100% in the laser groups and 70% to 77% and 92% to 97% in the expectant observation group.55–59 In an international survey of over 80 fetal treatment centers, when asked how they would manage uncomplicated stage I TTT, expectant management was the predominant recommendation (78%), followed by AR (11%), laser ablation (11%), and septostomy (1%).60 When examples of special patient circumstances were presented, either severe uterine overdistention with maternal discomfort and MVP 14 cm or there was advanced cervical change with cervical length of
