Review Article
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Twin-to-Twin Transfusion Syndrome: Prenatal Diagnosis and Treatment Ahmet A. Baschat, MB, BCh1
1 Department of Obstetrics, Gynecology and Reproductive Sciences,
University of Maryland School of Medicine, Baltimore, Maryland Am J Perinatol 2014;31:583–594.
Abstract
Keywords
► twin-to-twin transfusion syndrome ► prenatal diagnosis ► monochorionic twins ► fetoscopy ► laser ablation
Clinical Problem Twin-to-twin transfusion syndrome (TTTS) increases perinatal morbidity and mortality for 10 to 15% of monochorionic (MC) gestations. Pathophysiology MC gestations are at risk due to the angioarchitecture of the shared placenta, with anastomoses of varying type, size, and quantity. TTTS results from progression of a chronic perfusion imbalance across unbalanced placental anastomoses, typically arising between 15 and 26 weeks gestation. The resulting abnormal fetal blood volume levels and compensatory physiological responses lead to an increased risk for fetal death, end-organ damage, and preterm birth. Prenatal Diagnosis Surveillance with ultrasound is essential for detection and treatment. TTTS is diagnosed once polyhydramnios occurs in the recipient (maximal vertical fluid pocket [MVP] > 8 cm) and oligohydramnios in the donor (MVP < 2 cm). The Quintero et al method is commonly used for staging, utilizing the presence or absence of donor bladder filling, abnormal fetal Doppler values, fetal hydrops, and demise. Treatment Fetoscopic laser photocoagulation of placental anastomoses is an effective treatment addressing the underlying pathophysiology. Further research is needed to improve survival rates, reduce risks of fetoscopy, and gain understanding of the prediction, assessment, and optimization of long-term outcomes for TTTS survivors.
Monochorionic (MC) multiple gestations are at increased risk for adverse outcome, and the angioarchitecture of the shared placenta determines the type of complications that occur, as well as the options for treatment. The study of twin-to-twin transfusion syndrome (TTTS), a complication of MC placentation, demonstrates an important sequence of advances in perinatal medicine: the transition from pediatric to prenatal diagnostic criteria, the development of a prenatal prognostic tool, and prenatal therapy to address many of the important avenues for compromise. The aim of this review article is to provide a concise update on pathophysiology, clinical features, and management of pregnancies complicated by TTTS, in the context of these advances. In areas where evidence is lacking, we will high-
received December 16, 2013 accepted after revision February 10, 2014 published online May 23, 2014
Address for correspondence Richard M. Benoit, MD, MPH, Department of Obstetrics, Gynecology and Reproductive Sciences, University of Maryland School of Medicine, 22 South Greene Street, NE16, Baltimore, MD 21201 (e-mail: [email protected]).
light consensus opinions based on clinical experience and existing literature.1
Pathophysiology of TTTS TTTS complicates 10 to 15% of MC gestations with an overall incidence of 1 to 3 per 10,000 pregnancies.2 The 2012 US vital statistics data reported 3,952,841 registered births, with a twin birth rate of 33.1 per 1,000, or 130,839 twin pregnancies,3 among which an estimated 3,238, or 2 to 3% of all twin pairs would be expected to present with TTTS annually. The incidence rate of twin birth in the United States increased steadily from 1971 until leveling off in 2009, with 36% attributed to assisted reproduction.4 There is a two- to
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DOI http://dx.doi.org/ 10.1055/s-0034-1372428. ISSN 0735-1631.
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Richard M. Benoit, MD, MPH1
Twin-to-Twin Transfusion Syndrome
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fourfold increase in MC placentation with assisted reproductive technology, mainly attributable to the use of intracytoplasmic sperm injection (ICSI) and delayed embryo transfer times.5 Accordingly, the prevalence of TTTS is highest in health care settings with an increased rate of advanced maternal age and increased utilization of assisted reproductive technology (ART). The angioarchitecture of the MC placenta determines outcome and is characterized by individual placental territory size, cord insertion location, and the quantity, size, and directionality of intertwin anastomoses (►Fig. 1). Unbalanced blood flow across the placental intertwin anastomoses is the principal cause for TTTS and twin anemia/polycythemia sequence (TAPS), and has been implicated in twin reversed arterial perfusion sequence. Unequal placental share due to asymmetric location of the vascular equator is the underlying mechanism for selective intrauterine growth restriction (sIUGR).
Role of Placental Anastomoses in the Pathogenesis of TTTS All MC placentas have intertwin anastomoses, forming in the first trimester during linking of the embryonic and placental circulations and allowing intertwin transfer of volume, red blood cells, vasoactive substances, and hormones. Three principal types of these anastomoses exist, with either unidirectional or bidirectional flow. Unidirectional flow occurs from the arterial to the venous side across arteriovenous (A-V) anastomoses, existing in both directions (A-V for donor to recipient and V-A for recipient to donor). A-V anastomoses end in a shared cotyledon where the arterial villous circulation of one twin links to the venous villous return of the other
at the level of the intervillous space. Artery-to-artery (A-A) and vein-to-vein (V-V) anastomoses are thought to remain after villous involution. Accordingly, their connections are superficial and allow bidirectional blood flow, as there is no interposed villous vascular tree. The overall direction and magnitude of volume shift from twin to twin is determined by the types of connection, vessel calibers, and the pulse pressure in each vascular compartment, while the location of shared cotyledons defines the vascular equator and the division of placental territory for each twin. TTTS results from progressive unbalanced chronic perfusion of blood components from donor to recipient twin across placental anastomoses. Such unbalanced transfer is more likely in those MC placentas with a preponderance of unidirectional A-V anastomoses, coupled with a lack of superficial balancing A-A or V-V anastomoses, or when these bidirectional anastomoses are unusually small.6 In addition, small caliber deep capillary anastomoses may allow the transfer of vasoactive mediators, despite their lack of contribution to the volume imbalance of TTTS.7
Clinical Manifestations of TTTS The principal clinical feature of TTTS is evidence of hypervolemia in the recipient twin with concurrent evidence of hypovolemia in the donor twin, which may be further complicated by secondary cardiovascular abnormalities. Today, prenatal ultrasound allows for the accurate diagnosis of TTTS and staging of its severity. It is important to consider that the signs of hyper- and hypovolemia evolve during gestation, and accordingly the clinical picture may vary in the first and second trimesters.
Fig. 1 The angioarchitecture of the monochorionic placenta determines the type of complications that occur, as well as the method of treatment.
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In the first trimester, fetal urination only provides a small contribution to amniotic fluid (AF) volume. Accordingly, polyhydramnios and oligohydramnios are not as prominent as later in gestation. During a first trimester ultrasound, discordance of nuchal translucency thickness as well as ductus venosus and tricuspid valve flow abnormalities may be the only signs of volume imbalance, and are related to the clinical progression to TTTS with AF and growth discordance later in the second trimester.8 In the second trimester, the sequence of recipient polyuria and donor oliguria, with the associated finding of the twin polyhydramnios/oligohydramnios sequence, becomes the lead diagnostic criterion for TTTS (►Fig. 2). Once this diagnostic threshold has been reached, the obstetrical impact of accelerating polyhydramnios and the fetal cardiovascular manifestations define the risks for preterm birth, fetal endorgan damage and stillbirth, respectively. As TTTS evolves, the donor twin responds to the decreasing blood volume and renal perfusion by a compensatory increase in the activity of the renin-angiotensin system (RAS), producing vasoconstriction, oliguria, and oligohydramnios. Renal hypoperfusion results in renal tubular hypoplasia and atrophy. Decreased bladder distension occurs, with decreased frequency of bladder emptying, or complete absence of bladder filling in a 60-minute period. These findings may progress to oligohydramnios (less than a 2 cm maximal vertical fluid pocket [MVP]) or anhydramnios
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—often noted as a “stuck twin.” Abnormal umbilical artery findings, such as absent end-diastolic velocity, may also occur when placental share is unequal in the presence of TTTS (►Fig. 2). The recipient twin responds to hypervolemia by releasing atrial natriuretic peptide as a result of atrial distension. This increases urination with resulting polyhydramnios. Fetal natriuretic peptide and brain natriuretic peptide, both diuretics and potent vasodilators, promote polyuria and have been shown to be higher in the recipient twin, correlating with cardiac dysfunction.9 Despite a down regulation of renal RAS in response to hypervolemia, overall recipient renin levels are paradoxically elevated, postulated to result principally from recipient placental up-regulation, and potentially some local transfer across vascular connections from the donor, predisposing to cardiomyopathy and hypertension.10 Recipient hypervolemia and polyuria may be detected by ultrasound as bladder distension, failure of complete bladder emptying, and increasing AF volumes. Cardiovascular manifestations of TTTS result from the combination of intravascular volume changes and exposure to vasoactive mediators. The recipient fetus bears increased risk for myocardial dysfunction, including myocardial hypertrophy from volume overload and functional right outflow obstruction. Ultrasound may detect an increase in cardiac size, increased cardiothoracic ratio, and depressed myocardial performance index (►Fig. 3).
Fig. 2 Ultrasound findings representing staging for TTTS with the Quintero et al method. 21 The twin polyhydramnios and oligohydramnios sequence is the lead diagnostic criterion for TTTS, Stage I, while the absence of bladder filling for the donor is a criteria for Stage II TTTS. Critically abnormal Doppler findings are noted for Stage III, and fetal hydrops for Stage IV. TTTS, twin-to-twin transfusion syndrome. American Journal of Perinatology
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Twin-to-Twin Transfusion Syndrome
Twin-to-Twin Transfusion Syndrome
Benoit, Baschat
Fig. 3 Recipient cardiovascular manifestations of TTTS. Exam findings from a case under surveillance with development of TTTS at 26 weeks gestation. Panels A to C demonstrate recipient twin MPI progressively increased during course of surveillance and progression to TTTS, Stage IV. The MPI reflects global myocardial function, and may be calculated as the sum of isovolumetric contraction and relaxation times divided by the ejection time, and normal left ventricular MPI values are typically less than 0.45. 48 Panels E and F demonstrate abnormal Doppler findings for the recipient diagnosed with TTTS at 26 weeks gestation, with (E) umbilical vein pulsations and (F) reversal of the atrial wave of the ductus venosus. MPI, myocardial performance index; TTTS, twin-to-twin transfusion syndrome.
Cardiac dysfunction may also appear on fetal examinations as atrioventricular regurgitation, reversal of transverse arch blood flow direction, and fusion of the early-active phase waveforms of the atrioventricular inflow pattern (diastolic dysfunction). Subsequent possible increases in the Doppler indices of the ductus venous and the occurrence of umbilical venous pulsations have been associated with development of hydrops in the recipient twin. A paradoxical decrease in recipient fetal urination and AF levels may be caused by progressive decreased forward flow in a recipient if cardiac function deteriorates. Cardiovascular signs of TTTS can manifest independent of volume abnormalities.11 In the third trimester, fetal discordance of growth and fluid may occur, and uterine activity may further impact on placental dynamics. Maternal symptoms may also be present as polyhydramnios, may increase uterine distension, shorten cervical length, and lead to preterm labor. In addition, clinicians need to be aware of the potential for maternal mirror syndrome, a rare condition featuring maternal edema in association with fetal hydrops, and a serious risk to maternal and fetal morbidity.12 Maternal symptoms such as rapid onset of edema with respiratory or cardiac compromise should prompt assessment for fetal signs of TTTS. There is also a form of acute peripartum TTTS, featuring a hemoglobin discordance of > 8 g/dL without reticulocytosis American Journal of Perinatology
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or hypovolemic shock, which has been described to occur in 2.5% of MC twin gestations and occurs more often in association with vaginal delivery and first order twin birth.13 This form of TTTS represents the neonatal diagnosis for this condition that was widely used before the development of prenatal diagnostic criteria.
Clinical Surveillance and Diagnostic Criteria for TTTS All twin pregnancies are considered “at risk” until placentation is determined. Assignment of chorionicity is accurately achievable in the first trimester. Among MC gestations, increased surveillance is recommended, given that the onset and progression of TTTS are variable, and early diagnosis with prompt treatment prolongs gestational age and improves survival rates. The diagnosis of TTTS is based on the detection of polyhydramnios/oligohydramnios sequence in a MC twin pair. Strict criteria are important to distinguish TTTS from AF discordance, or sIUGR. The U.S. definition of polyhydramnios in the recipient is an MVP of 8 cm or more. The European definition uses an MVP of greater than 10 cm after 20 weeks gestation. Oligohydramnios in the donor is noted when the MVP is less than 2 cm. Discordant fetal bladders with
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markedly enlarged bladder in the recipient and a small bladder in the donor during most of the examination may also be observed (►Figs. 2 and 3). Biweekly ultrasound assessments starting at 16 weeks gestation are recommended for MC gestations to detection and subsequently stage TTTS. These examinations include twin maximal vertical AF pockets, assessment of fetal growth, and bladder size.1 Weekly assessment is recommended if clinical suspicion for progression to TTTS is increased, such as with AF discordance.1 A Doppler profile for each fetus and a maternal cervical length measurement complete the staging assessment and assist with management decisions once TTTS is detected. Doppler profiles for both fetuses should include umbilical artery, ductus venosus, and umbilical vein Doppler as these parameters define the severity of TTTS. In addition, middle cerebral artery peak systolic velocity (MCA-PSV) measurements are necessary to diagnose or distinguish between coexisting TAPS (►Fig. 4). In the absence of diagnostic signs, prediction of which MC gestation will develop TTTS is limited and requires ongoing ultrasound surveillance until delivery to detect late onset complications, although ultrasound parameters and biomarkers are being investigated for this purpose. Findings indicating increased risk for progression to TTTS include NT discordance with abnormal ductus venosus flow,8 AF discordance and/or fetal growth discordance of 25% or more,14 intertwin abdominal circumference difference > 10% between 14 and 22 weeks gestation,15 and certain cardiac parameters.11
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Surveillance of MC twins must also account for the potential for twin anemia, TAPS, which complicates up to 5% of MC pregnancies as a spontaneous occurrence. TAPS can also complicate true TTTS and also affects up to 13% of TTTS MC pregnancies after laser therapy.16 TAPS is diagnosed prenatally with the use of Doppler measurements of the MCA-PSV. TAPS is diagnosed if MCA-PSV greater than 1.5 MoM is observed in the setting of a cotwin with MCA-PSV less than 1.0 MoM, absent findings of TTTS, such as fluid volume imbalance.16 Although fetal size discrepancy is not required for the diagnosis of TTTS, fetal growth assessments are integral to effective serial surveillance because unequal placental sharing in MC twins may lead to isolated discordant growth, defined as an intertwin size difference of 25%. Up to 20% of pregnancies complicated by growth discordance subsequently develop TTTS, and 30% of pregnancies with late onset growth discordance are at risk for significant hemoglobin discordance developing in the setting of equal placental share but small unidirectional anastomoses.17 sIUGR indicates that the estimated fetal weight of the smaller twin falls below the 10th percentile. AF discordance may also occur, although there is the absence of polyhydramnios in the normally grown twin. Three patterns of sIUGR have been described based on placental share and umbilical artery flow patterns, with variable rates of unanticipated stillbirth as high as 15%.18 A discussion of sIUGR is beyond the scope of this article, although it is important to consider this diagnosis in the surveillance of MC pregnancies, particularly since it may occur following the treatment of TTTS.
Fig. 4 Clinical management schematic for MC gestations with timing of typical surveillance methods and potential complications. MC, monochorionic. American Journal of Perinatology
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Twin-to-Twin Transfusion Syndrome
Twin-to-Twin Transfusion Syndrome
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As MC gestations are also at increased risk for aneuploidy and congenital anomalies, patients should receive genetic counseling and second trimester detailed fetal anatomical assessments including fetal echocardiography. Genotypic and phenotypic discordances in MC twins are related to complex and dynamic interactions between genetic, epigenetic, and environmental factors.19 Overall, concordant congenital abnormalities are found in 10% of all MC twins, while an additional 6% of MC twins can exhibit discordance for structural anomalies.19 Cardiac defects are most frequent, however, abnormalities of the central nervous system, as well as cloacal and urogenital anomalies can occur. Discordance of fetal brain abnormalities may also occur in the setting of severe TTTS, sIUGR, and in cases of single twin demise (►Fig. 5). Abnormal brain findings may evolve to include ventriculomegaly, arrest of head growth, or frank hydrancephaly. Such cases may also arise following laser surgery, where acute changes related to vascular reperfusion injury may occur. On the maternal side, the surveillance of the MC twin gestation includes symptom assessment related to polyhydramnios along with ultrasound examination of cervical length due to an increased risk for preterm birth above the background incidence. The risk for preterm birth correlates independently with shortened cervical length in TTTS cases,20 and gestational age at delivery is the strongest predictor of outcome.
Prognostic Assessment of TTTS Disease Severity Quintero et al developed the current commonly used staging system for TTTS by describing sonographic and clinical parameters to delineate a sequence of events representing disease progression.21 Stage I is diagnosed when the diagnostic criteria of fluid imbalance are met, the bladder remains visible in the donor, and normal Doppler findings are observed. In Stage II, the bladder is no longer visible in the donor, and Stage III is noted when a critically abnormal Doppler in either twin is observed, including absent-reverse diastolic flow in the donor or recipient umbilical artery,
absent/reverse flow in the ductus venosus, or pulsatile flow in the umbilical vein. Stage IV is defined as the presence of hydrops is present in either fetus, while Stage V indicates the demise of one or both twins. Among patients referred for fetal therapy for suspected TTTS, 59% were referred after 20 weeks gestation, and the distribution of stages at the time of diagnosis following referral was as follows: Quintero et al Stage I in 28 (11%), Stage II in 50 (20%), Stage III in 150 (60%), Stage IV in 15 (6%), and Stage V in 6 (2%).22 This pattern demonstrates the need for improved early surveillance with the goal of achieving earlier referral.22 Staging of TTTS with the goal of predicting disease severity and prognosis is challenging due to the variation in presenting features, lack of predictable disease progression, and the potential for different disease impact on recipient and donor. Survival outcomes based on stage have been supported by observational studies, although most recent studies show similar outcomes across all stages treated with laser surgery.23 Alternate staging systems incorporating cardiac function parameters have been proposed.11 Although such assessments provide information about the natural history of TTTS, given the reversible nature of the cardiac findings, there is currently insufficient evidence to prove their clinical value in predicting fetal survival postlaser treatment. Currently, the prediction of improved survival at earlier Quintero et al stages is not significantly enhanced by more elaborate staging systems and accordingly, these have not replaced the original method described by Quintero et al. Placental share and velamentous cord insertion (VCI) affect the outcome of MC pregnancies and TTTS, although these factors are not causative of TTTS. The severity of birthweight discordance correlates with unequal placental share and VCI, and may also vary based on types of anastomoses present and the potential for nutrient exchange between the fetuses with differing placental shares.24 The presence of a VCI correlates with increased the risk of small for gestational age (SGA), severe birthweight discordance, intrauterine fetal demise (IUFD), and lower gestational age at birth, for MC twin gestations both with and without TTTS.24 Donor survival rates following laser surgery are worsened with abnormally small placental share, and among TTTS cases, VCI occurs more often in the donor.24 Therefore, the presence of VCI may be a useful prognostic indicator in MC twins and TTTS cases postlaser treatment. In addition, the first trimester detection of VCI is possible, allowing for increased surveillance.24 MCA Doppler has emerged as an important component of the surveillance and staging examination for TTTS. Its diagnostic accuracy in the identification of TAPS in complex TTTS cases and after laser therapy is well established. The presence of elevated MCA-PSV in the recipient preoperatively is associated with increased risk for IUFD, although this finding is only noted in only 3% of TTTS recipients at diagnosis.25
Management of TTTS Fig. 5 Evidence of fetal brain injury, with cortical mantle thinning and ventriculomegaly noted bilaterally, occurring following demise of a cotwin in a monochorionic gestation. American Journal of Perinatology
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Untreated TTTS presenting in the second trimester has a perinatal mortality rate of almost 90%.26 Clinical
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management options for established TTTS include fetoscopic laser surgery, amnioreduction, selective reduction, or pregnancy termination. Factors determining the management approach include gestational age at diagnosis, cervical length, and technical factors impacting fetoscopy, such as placental location, cord insertion sites, and maternal anatomy. For Stage I TTTS, treatment remains an area of clinical equipoise, and a randomized trial is currently underway, comparing conservative management and primary laser therapy (ClinicalTrials.gov: NCT01220011). Until the results of this trial are reported, patients at Stage I can be offered fetoscopic laser or conservative management. An estimated 10% of patients with Stage I will show progression.27 These patients and those with Stage I disease with polyhydramniosrelated symptoms or cervical shortening are candidates for laser therapy. For Stages II to IV diagnosed between 16 and 26 weeks gestation, fetoscopic laser photocoagulation of placental anastomoses is the primary treatment.28 Clinical evidence supports, in selected cases, offering laser outside of these gestational ages with similar beneficial results,29 which requires special exemption by the Food and Drug Administration due to regulations regarding the use of fetoscopes in the United States. The laser procedure begins with the introduction of a fetoscope into the recipient’s sac to identify and coagulate all intertwin anastomoses present along the vascular equator with a laser fiber (Nd:YAG or diode). The proce-
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dure includes amnioreduction before the removal of the fetoscope. Innovation of techniques in fetoscopic laser photocoagulation has occurred with increasing experience and improved understanding of the angioarchitecture of the MC placenta (►Fig. 6). The nonselective laser occlusion of vessels initially described30 has been replaced by techniques selectively targeting the anastomotic vessels in a sequential fashion (sequential selective laser photocoagulation of communicating vessels).31 A recent advance targets the entire vascular equator with a “Solomon” technique to dichorionize the placenta.32 Evidence for improved outcomes with these techniques have been reported,31,32 while the use of equatorial laser dichorionization is currently being investigated in a clinical randomized trial (www.trialregister.nl, NTR 1245). When technically achieved, equatorial dichorionization converts the MC circulation into two independent vascular systems, reversing the hemodynamic disturbances associated with TTTS in the days following treatment. This also reduces the risk to the cotwin in the event of a single demise, and can reduce the recurrence of TTTS and the occurrence of TAPS postlaser, without increasing adverse outcomes32 (►Fig. 7). There are no formal contraindications to laser therapy, although a short cervical length (less than 15 mm) may indicate a higher risk of preterm delivery and may require consideration for a cervical cerclage.33 Laser surgery should also be offered before amnioreduction, which may be
Fig. 6 Schematic representation of laser techniques in the treatment of TTTS. The nonselective method initially described occludes all vessels crossing the intertwin membrane. 30 Selective laser ablation of placental anastomoses (X only) shifts the technique to occlude anastomoses where they occur, which thereby define the vascular equator, or shared zone of the placenta. The sequential selective laser photocoagulation of communicating vessels, not depicted, ablates the donor A-V first, to allow for hemodynamic improvement in volume status for the donor. 31 The equatorial laser dichorionization technique then further separates the fetal circulations by applying laser along chorionic plate in a virtual line connecting the ablated anastomoses, the vascular equator32 (shaded areas). A-V, arteriovenous; TTTS, twin-to-twin transfusion syndrome. American Journal of Perinatology
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Twin-to-Twin Transfusion Syndrome
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Fig. 7 Fetoscopic laser photocoagulation of placental anastomoses with equatorial dichorionization. Panel A includes a V-V anastomosis between donor and recipient. Panel B includes the laser fiber in view, in preparation for selective ablation in panel C. Panel D shows the ablation of the intertwin vascular equator on the right side of the image. V-V, vein-to-vein.
associated with complications such as rupture of membranes and inadvertent septostomy and may decrease visibility due to intra-amniotic bleeding. These complications can reduce the success of the fetoscopic approach. As a second-line therapy, serial amniodrainage may be considered where laser treatment is not possible due to technical or regulatory restrictions. Amnioreduction is proposed to prolong pregnancy by reducing the risks of polyhydramnios, decreasing maternal discomfort, and reducing transplacental pressure on the fetal circulation. Selective feticide remains an important technique and management option in certain cases, such as with discordance for malformations or cerebral injury. Laser photocoagulation of the umbilical cord is the technique most often used. Selective feticide should not be considered a first-line therapy for TTTS given the improvements in outcome that have been realized with laser treatment. Nondirective counseling offering the option for selective feticide and pregnancy termination is a component of complete care, particularly given the unpredictability of neurodevelopmental outcome in the setting of unanticipated stillbirth or when TTTS complicates higher order multiples. For Stage V patients, with the death of one MC twin, outcomes for the surviving cotwin include a 12% risk for subsequent demise, an 18% risk for neurological abnormality, and a 68% risk of preterm birth.34 Evaluation of the surviving twin includes imaging of the fetal brain (ultrasound and magnetic resonance imaging [MRI]), and MCA Doppler to assess for anemia. In acute settings, fetal transfusion may be offered if evidence of fetal anemia is noted on MCA Doppler within the first 24 to 48 hours of the event; however, improvement in intact survival is unproven with this approach.35 A retrospective study of brain injury following MC American Journal of Perinatology
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cotwin demise demonstrated that most of the cases of abnormal brain findings on ultrasound were identified only after 1 to 2 weeks had passed, suggesting the importance of continued follow-up and serial imaging.36 MRI, particularly diffusion-weighted sequence MRI, has shown promise in detecting earlier changes suggestive of fetal brain injury,37 although it remains to be determined if these findings consistently correlate with long-term outcome. Evidence of fetal brain injury on ultrasound is correlated with poor prognosis, whereas absence of abnormal imaging findings is promising36; however, cautious counseling is warranted given that it cannot assure normal long-term neurodevelopmental outcome. Multiple assessments and decision points may occur in the course of TTTS management, utilizing information from diagnostic and staging examinations, fetoscopy, and postlaser ultrasound surveillance. Fetoscopic assessment of the quality of laser procedure and placental share may aid in predicting disease progression or complications. In addition, ultrasound findings posttreatment assist in documenting resolution of the condition and also assess for risk factors that may impact eventual outcome. These include a shortened cervical length, IUGR, cerebral abnormalities, recurrence of TTTS, TAPS, or fetal demise. Though our ability to predict the risk of fetal demise following treatment is limited, preoperative and perioperative methods of evaluating risk have been reported.25 Clinical findings and patient counseling determine the best location for follow-up, the need for referral to a fetal medicine center, and the frequency of examinations. The specialist center provides comprehensive patient education on the condition, potential outcomes, and treatment options, while customizing support for patient-specific cultural factors of risk aversion and acceptance of medical counseling.
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Delivery management of twin-to-twin transfusion remains guided by retrospective study, and case-by-case details often determine a course of action. Stillbirth risk is increased among MC gestations,38 particularly for those affected by TTTS, and delivery is recommended by 34 to 36 weeks gestation, typically by cesarean section.
Outcomes with Treatment of TTTS Outcomes with treatment of TTTS reflect maternal and fetal characteristics at the time of diagnosis, as well as the mode of therapy. Treatment complications, gestational age at delivery, survival rates for one or both twins, and rate of short- and long-term morbidity among survivors are important outcome parameters for patient counseling. Survival at 6 months of life for at least one twin ranges from 76 to 88% following laser treatment for TTTS.28,32 Stagebased reports of outcomes for TTTS suggest similar results with treatment for laser, regardless of stage at diagnosis.23,39 The probability of two survivors at 6 months of life following laser treatment differs across studies based on methodology, ranging from 36 to 68%.28,32 The reported incidence of severe neurodevelopmental impairment at 2 to 5 years of age is 13 to 18%, with a cerebral palsy rate of 6 to 7%.40,41 Potential complications after laser include intrauterine fetal death of either fetus (13–30%) and preterm rupture of membranes (10%).28 Persistence of overt TTTS due to anastomoses missed during surgery (2–14%) and TAPS (2–13%) can also occur. The frequency of these complications depends on the ability to complete the ablation of anastomoses and the equator, which can vary due to placental location and operator experience. Repeat fetoscopic laser procedures may be required where progression of TTTS or TAPS occurs. In contrast, serial amniodrainage for the treatment of severe TTTS before 26 weeks’ gestation has a reported survival rate of 51 to 60% for at least one fetus28 and a rate of neurological handicap of 29%.42 Amniodrainage is also associated with significant risks including septostomy and rupture of membranes.43 Gestational age at delivery for TTTS patients following laser treatment has been consistently reported to be near a median of 32 to 33 weeks gestation (excluding higher order multiples), with improvement demonstrated as laser techniques and operator experience evolve.28,32,39 Results with serial amnioreduction reveal an earlier average gestational age at delivery of 29 weeks.28 For survivors of TTTS, structural heart disease is more prevalent, and among TTTS pairs, 11 to 13% of recipients have congenital heart disease.44 For recipients, chronic right-sided volume overload and vasoactive mediators may contribute to muscular hypertrophy and reduced anterograde flow in the right ventricular outflow tract. This may lead to the development of pulmonary stenosis.44 Although laser may address the cardiac changes directly by reducing volume overload in the recipient, amnioreduction does not improve the cardiac dysfunction, which may progress until delivery. However, recipient pulmonary stenosis occurs after both types of
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therapy, indicating a potential role for early imprinting, which may require novel approaches to address. The prospect for normal neurodevelopmental outcome among offspring of a TTTS pregnancy is an essential component of patient counseling and treatment selection. Although perinatal outcomes are improved with laser versus amnioreduction, less evidence exists regarding long-term neurodevelopmental outcomes.45 Level I evidence in support of laser over amnioreduction is lacking and the window for obtaining such research has passed, given the preponderance of evidence showing the survival benefit to laser. The latest Cochrane review meta-analysis published in 2008 concluded that laser results in a decreased mortality of both infants per pregnancy (relative risk [RR], 0.49; 95% confidence interval [CI], 0.30–0.79, one trial), less perinatal death (RR, 0.59; 95% CI, 0.0.40–0.87 adjusted for cluster, one trial) and less neonatal death (RR, 0.29; 95% CI, 0.14–0.61).45 The study reported no difference in rates of neurological abnormality in survivors at 6 months of age between the laser and amnioreduction groups. van Klink et al also performed a systematic review directly comparing amnioreduction with laser surgery on rates of severe cerebral injury and neurodevelopmental impairment in TTTS.46 The five studies included in the analysis (three comparative studies plus two follow-up studies from the Eurofetus trial) revealed an odds ratio of 7.69 (95% CI, 2.7– 20) for severe cerebral injury to occur in survivors of TTTS postamnioreduction versus laser. In the postlaser therapy group, the percentage of survivors with cerebral injury ranged from 0 to 7%, the risk for cerebral palsy at 6 years of age was 13%, and the rate of developmental delay was 5.5%.28,47 The analysis concluded that amnioreduction is associated with an increased risk for cerebral injury compared with laser surgery, although insufficient data were available to assess long-term neurodevelopmental outcomes.46 Studies showing little or no benefit to laser treatment versus amnioreduction in long-term neurodevelopmental outcome have been based on treatment with selective laser ablation.40 The newest equatorial laser dichorionization technique provides enhanced benefit by addressing the vascular
Fig. 8 Comparison of reported survival rates following treatment for TTTS at 6 months of age. Both studies included all stages of TTTS. 28,32 TTTS, twin-to-twin transfusion syndrome. American Journal of Perinatology
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Twin-to-Twin Transfusion Syndrome
Twin-to-Twin Transfusion Syndrome
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anastomoses causing TTTS in addition to the vascular equator. This shortens the exposure of the fetuses to the impact of TTTS, protects the survivor in event of cotwin demise, and prolongs the gestational age until delivery, which remains the most important predictor of neurological outcome. In addition, when compared with prior published outcomes, the equatorial technique has provided outcomes with improved survivor rates (►Fig. 8). Unfortunately, no pregnancy is without a baseline risk for preterm birth or developmental delay, and the risk is highest in MC twin as compared with singletons or dichorionic gestations. A prospective study of a cohort of 136 pairs of MC twins that were followed up from the first trimester until 2 years of age revealed a rate of 10% for neurodevelopmental impairment alone and a rate of a composite outcome of 22% for death or impairment.41 The risks of death and impairment were increased with TTTS and assisted conception. The rate of cerebral palsy was 2%, 10-fold higher than background rates. TTTS accounted for one in five infants with impairment and for the majority of infants with cerebral palsy in the cohort. TTTS may reverse once successfully treated, with no longterm impact on survivors independent of gestational age. In general, regardless of the treatment approach for TTTS, the increased risks of preterm birth and antenatal brain injury, caused by the disease or the reperfusion associated with laser, necessitate cranial ultrasound examination after birth and routine neurodevelopmental follow-up.41
Conclusion
7 van den Wijngaard JP, Lopriore E, van der Salm SM, et al. Deep-
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TTTS is a complication of MC placentation with a well-developed clinical screening, detection, and treatment paradigm that improves outcomes. Advances in the management of TTTS, resulting through the cooperative work of international teams of investigators, serve as an important example of progress in perinatal medicine, and provide hope for the future. Given the current limitations in ability to predict the onset of the condition, and the challenge to improve both short and long outcomes with treatment, continued investigation is paramount.
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References 1 Baschat A, Chmait RH, Deprest J, et al; WAPM Consensus Group on
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Twin-to-Twin Transfusion. Twin-to-twin transfusion syndrome (TTTS). J Perinat Med 2011;39(2):107–112 Blickstein I. Monochorionicity in perspective. Ultrasound Obstet Gynecol 2006;27(3):235–238 Martin J, Hamilton B, Osterman M, Curtin S, Mathews TJ. Births: final data for 2012. Natl Vital Stat Rep 2013;62(9):1–27 Kulkarni AD, Jamieson DJ, Jones HW Jr, et al. Fertility treatments and multiple births in the United States. N Engl J Med 2013; 369(23):2218–2225 Knopman J, Krey LC, Lee J, Fino ME, Novetsky AP, Noyes N. Monozygotic twinning: an eight-year experience at a large IVF center. Fertil Steril 2010;94(2):502–510 De Paepe ME, Shapiro S, Greco D, et al. Placental markers of twinto-twin transfusion syndrome in diamniotic-monochorionic twins: A morphometric analysis of deep artery-to-vein anastomoses. Placenta 2010;31(4):269–276
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hidden anastomoses in monochorionic twin placentae are harmless. Prenat Diagn 2007;27(3):233–239 Matias A, Montenegro N, Loureiro T, et al. Screening for twin-twin transfusion syndrome at 11-14 weeks of pregnancy: the key role of ductus venosus blood flow assessment. Ultrasound Obstet Gynecol 2010;35(2):142–148 Bajoria R, Ward S, Chatterjee R. Natriuretic peptides in the pathogenesis of cardiac dysfunction in the recipient fetus of twin-twin transfusion syndrome. Am J Obstet Gynecol 2002; 186(1):121–127 Galea P, Barigye O, Wee L, Jain V, Sullivan M, Fisk NM. The placenta contributes to activation of the renin angiotensin system in twin-twin transfusion syndrome. Placenta 2008; 29(8):734–742 Rychik J, Tian Z, Bebbington M, et al. The twin-twin transfusion syndrome: spectrum of cardiovascular abnormality and development of a cardiovascular score to assess severity of disease. Am J Obstet Gynecol 2007;197(4):e1–e8 Braun T, Brauer M, Fuchs I, et al. Mirror syndrome: a systematic review of fetal associated conditions, maternal presentation and perinatal outcome. Fetal Diagn Ther 2010;27(4):191–203 Lopriore E, Holtkamp N, Sueters M, Middeldorp J, Walther F, Oepkes D. Acute peripartum twin-twin transfusion syndrome: Incidence, risk factors, placental characteristics and neonatal outcome. J Obstet Gynaecol Res 2014;40(1):18–24 Carver A, Haeri S, Moldenhauer J, Wolfe HM, Goodnight W. Monochorionic diamniotic twin pregnancy: timing and duration of sonographic surveillance for detection of twin-twin transfusion syndrome. J Ultrasound Med 2011;30(3):297–301 O’Connor C, McAuliffe FM, Breathnach FM, et al; Perinatal Ireland Research Consortium. Prediction of outcome in twin pregnancy with first and early second trimester ultrasound. J Matern Fetal Neonatal Med 2013;26(10):1030–1035 Slaghekke F, Kist WJ, Oepkes D, et al. Twin anemia-polycythemia sequence: diagnostic criteria, classification, perinatal management and outcome. Fetal Diagn Ther 2010;27(4):181–190 Lewi L, Gucciardo L, Huber A, et al. Clinical outcome and placental characteristics of monochorionic diamniotic twin pairs with earlyand late-onset discordant growth. Am J Obstet Gynecol 2008; 199(5):e1–e7 Gratacós E, Lewi L, Muñoz B, et al. A classification system for selective intrauterine growth restriction in monochorionic pregnancies according to umbilical artery Doppler flow in the smaller twin. Ultrasound Obstet Gynecol 2007;30(1):28–34 Cao AMG. Phenotypic and genotypic discordance in monozygotic twins. In: Blickstein I, Keith LG, eds. Multiple Pregnancy: Epidemiology, Gestatio, and Perinatal Outcome. UK: Taylor & Francis; 2005:226–232 Robyr R, Boulvain M, Lewi L, et al. Cervical length as a prognostic factor for preterm delivery in twin-to-twin transfusion syndrome treated by fetoscopic laser coagulation of chorionic plate anastomoses. Ultrasound Obstet Gynecol 2005;25(1):37–41 Quintero RA, Morales WJ, Allen MH, Bornick PW, Johnson PK, Kruger M. Staging of twin-twin transfusion syndrome. J Perinatol 1999;19(8 Pt 1):550–555 Gandhi M, Papanna R, Teach M, Johnson A, Moise KJ Jr. Suspected twin-twin transfusion syndrome: how often is the diagnosis correct and referral timely? J Ultrasound Med 2012;31(6): 941–945 Rossi AC, D’Addario V. The efficacy of Quintero staging system to assess severity of twin-twin transfusion syndrome treated with laser therapy: a systematic review with meta-analysis. Am J Perinatol 2009;26(7):537–544 Costa-Castro T, De Villiers S, Montenegro N, et al. Velamentous cord insertion in monochorionic twins with or without twin-twin transfusion syndrome: does it matter? Placenta 2013;34(11): 1053–1058
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25 Eixarch E, Valsky D, Deprest J, et al. Preoperative prediction of the
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individualized risk of early fetal death after laser therapy in twinto-twin transfusion syndrome. Prenat Diagn 2013:1–6 Urig MA, Clewell WH, Elliott JP. Twin-twin transfusion syndrome. Am J Obstet Gynecol 1990;163(5 Pt 1):1522–1526 Rossi AC, D’Addario V. Survival outcomes of twin-twin transfusion syndrome stage I: a systematic review of literature. Am J Perinatol 2013;30(1):5–10 Senat MV, Deprest J, Boulvain M, Paupe A, Winer N, Ville Y. Endoscopic laser surgery versus serial amnioreduction for severe twin-to-twin transfusion syndrome. N Engl J Med 2004;351(2): 136–144 Baud D, Windrim R, Keunen J, et al. Fetoscopic laser therapy for twin-twin transfusion syndrome before 17 and after 26 weeks’ gestation. Am J Obstet Gynecol 2013;208(3):e1–e7 De Lia JE, Cruikshank DP, Keye WR Jr. Fetoscopic neodymium:YAG laser occlusion of placental vessels in severe twin-twin transfusion syndrome. Obstet Gynecol 1990;75(6):1046–1053 Quintero RA, Ishii K, Chmait RH, Bornick PW, Allen MH, Kontopoulos EV. Sequential selective laser photocoagulation of communicating vessels in twin-twin transfusion syndrome. J Matern Fetal Neonatal Med 2007;20(10):763–768 Baschat AA, Barber J, Pedersen N, Turan OM, Harman CR. Outcome after fetoscopic selective laser ablation of placental anastomoses vs equatorial laser dichorionization for the treatment of twin-to-twin transfusion syndrome. Am J Obstet Gynecol 2013;209(3):e1–e8 Salomon LJ, Nasr B, Nizard J, et al. Emergency cerclage in cases of twin-to-twin transfusion syndrome with a short cervix at the time of surgery and relationship to perinatal outcome. Prenat Diagn 2008;28(13):1256–1261 Ong SS, Zamora J, Khan KS, Kilby MD. Prognosis for the co-twin following single-twin death: a systematic review. BJOG 2006; 113(9):992–998 Senat MV, Loizeau S, Couderc S, Bernard JP, Ville Y. The value of middle cerebral artery peak systolic velocity in the diagnosis of fetal anemia after intrauterine death of one monochorionic twin. Am J Obstet Gynecol 2003;189(5):1320–1324 Simonazzi G, Segata M, Ghi T, et al. Accurate neurosonographic prediction of brain injury in the surviving fetus after the death of a monochorionic cotwin. Ultrasound Obstet Gynecol 2006;27(5): 517–521 Weisz B, Hoffmann C, Ben-Baruch S, et al. Early detection of severe brain lesions after fetoscopic laser treatment in twin-twin transfusion syndrome by diffusion weighted sequence MRI (e-pub ahead of print). Ultrasound Obstet Gynecol 2013; doi: 10.1002/ uog.13283
delivery in monochorionic diamniotic twin pregnancies 32 weeks of gestation: a multicentre retrospective cohort study. BJOG 2011;118(9):1090–1097 Chmait RH, Kontopoulos EV, Korst LM, Llanes A, Petisco I, Quintero RA. Stage-based outcomes of 682 consecutive cases of twin-twin transfusion syndrome treated with laser surgery: the USFetus experience. Am J Obstet Gynecol 2011;204(5):e1–e6 Lenclen R, Ciarlo G, Paupe A, Bussieres L, Ville Y. Neurodevelopmental outcome at 2 years in children born preterm treated by amnioreduction or fetoscopic laser surgery for twin-to-twin transfusion syndrome: comparison with dichorionic twins. Am J Obstet Gynecol 2009;201(3):e1–e5 Ortibus E, Lopriore E, Deprest J, et al. The pregnancy and long-term neurodevelopmental outcome of monochorionic diamniotic twin gestations: a multicenter prospective cohort study from the first trimester onward. Am J Obstet Gynecol 2009;200(5):e1–e8 Rossi AC, D’Addario V. Laser therapy and serial amnioreduction as treatment for twin-twin transfusion syndrome: a metaanalysis and review of literature. Am J Obstet Gynecol 2008;198(2): 147–152 Mari G, Roberts A, Detti L, et al. Perinatal morbidity and mortality rates in severe twin-twin transfusion syndrome: results of the International Amnioreduction Registry. Am J Obstet Gynecol 2001; 185(3):708–715 Herberg U, Gross W, Bartmann P, Banek CS, Hecher K, Breuer J. Long term cardiac follow up of severe twin to twin transfusion syndrome after intrauterine laser coagulation. Heart 2006;92(1): 95–100 Roberts D, Gates S, Kilby M, Neilson JP. Interventions for twin-twin transfusion syndrome: a Cochrane review. Ultrasound Obstet Gynecol 2008;31(6):701–711 van Klink JM, Koopman HM, van Zwet EW, Oepkes D, Walther FJ, Lopriore E. Cerebral injury and neurodevelopmental impairment after amnioreduction versus laser surgery in twin-twin transfusion syndrome: a systematic review and meta-analysis. Fetal Diagn Ther 2013;33(2):81–89 Salomon LJ, Ortqvist L, Aegerter P, et al. Long-term developmental follow-up of infants who participated in a randomized clinical trial of amniocentesis vs laser photocoagulation for the treatment of twin-to-twin transfusion syndrome. Am J Obstet Gynecol 2010; 203(5):e1–e7 Hernandez-Andrade E, Figueroa-Diesel H, Kottman C, et al. Gestational-age-adjusted reference values for the modified myocardial performance index for evaluation of fetal left cardiac function. Ultrasound Obstet Gynecol 2007;29(3):321–325
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Twin-to-Twin Transfusion Syndrome: Prenatal Diagnosis and Treatment Ahmet A. Baschat, MB, BCh1
1 Department of Obstetrics, Gynecology and Reproductive Sciences,
University of Maryland School of Medicine, Baltimore, Maryland Am J Perinatol 2014;31:583–594.
Abstract
Keywords
► twin-to-twin transfusion syndrome ► prenatal diagnosis ► monochorionic twins ► fetoscopy ► laser ablation
Clinical Problem Twin-to-twin transfusion syndrome (TTTS) increases perinatal morbidity and mortality for 10 to 15% of monochorionic (MC) gestations. Pathophysiology MC gestations are at risk due to the angioarchitecture of the shared placenta, with anastomoses of varying type, size, and quantity. TTTS results from progression of a chronic perfusion imbalance across unbalanced placental anastomoses, typically arising between 15 and 26 weeks gestation. The resulting abnormal fetal blood volume levels and compensatory physiological responses lead to an increased risk for fetal death, end-organ damage, and preterm birth. Prenatal Diagnosis Surveillance with ultrasound is essential for detection and treatment. TTTS is diagnosed once polyhydramnios occurs in the recipient (maximal vertical fluid pocket [MVP] > 8 cm) and oligohydramnios in the donor (MVP < 2 cm). The Quintero et al method is commonly used for staging, utilizing the presence or absence of donor bladder filling, abnormal fetal Doppler values, fetal hydrops, and demise. Treatment Fetoscopic laser photocoagulation of placental anastomoses is an effective treatment addressing the underlying pathophysiology. Further research is needed to improve survival rates, reduce risks of fetoscopy, and gain understanding of the prediction, assessment, and optimization of long-term outcomes for TTTS survivors.
Monochorionic (MC) multiple gestations are at increased risk for adverse outcome, and the angioarchitecture of the shared placenta determines the type of complications that occur, as well as the options for treatment. The study of twin-to-twin transfusion syndrome (TTTS), a complication of MC placentation, demonstrates an important sequence of advances in perinatal medicine: the transition from pediatric to prenatal diagnostic criteria, the development of a prenatal prognostic tool, and prenatal therapy to address many of the important avenues for compromise. The aim of this review article is to provide a concise update on pathophysiology, clinical features, and management of pregnancies complicated by TTTS, in the context of these advances. In areas where evidence is lacking, we will high-
received December 16, 2013 accepted after revision February 10, 2014 published online May 23, 2014
Address for correspondence Richard M. Benoit, MD, MPH, Department of Obstetrics, Gynecology and Reproductive Sciences, University of Maryland School of Medicine, 22 South Greene Street, NE16, Baltimore, MD 21201 (e-mail: [email protected]).
light consensus opinions based on clinical experience and existing literature.1
Pathophysiology of TTTS TTTS complicates 10 to 15% of MC gestations with an overall incidence of 1 to 3 per 10,000 pregnancies.2 The 2012 US vital statistics data reported 3,952,841 registered births, with a twin birth rate of 33.1 per 1,000, or 130,839 twin pregnancies,3 among which an estimated 3,238, or 2 to 3% of all twin pairs would be expected to present with TTTS annually. The incidence rate of twin birth in the United States increased steadily from 1971 until leveling off in 2009, with 36% attributed to assisted reproduction.4 There is a two- to
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DOI http://dx.doi.org/ 10.1055/s-0034-1372428. ISSN 0735-1631.
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Richard M. Benoit, MD, MPH1
Twin-to-Twin Transfusion Syndrome
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fourfold increase in MC placentation with assisted reproductive technology, mainly attributable to the use of intracytoplasmic sperm injection (ICSI) and delayed embryo transfer times.5 Accordingly, the prevalence of TTTS is highest in health care settings with an increased rate of advanced maternal age and increased utilization of assisted reproductive technology (ART). The angioarchitecture of the MC placenta determines outcome and is characterized by individual placental territory size, cord insertion location, and the quantity, size, and directionality of intertwin anastomoses (►Fig. 1). Unbalanced blood flow across the placental intertwin anastomoses is the principal cause for TTTS and twin anemia/polycythemia sequence (TAPS), and has been implicated in twin reversed arterial perfusion sequence. Unequal placental share due to asymmetric location of the vascular equator is the underlying mechanism for selective intrauterine growth restriction (sIUGR).
Role of Placental Anastomoses in the Pathogenesis of TTTS All MC placentas have intertwin anastomoses, forming in the first trimester during linking of the embryonic and placental circulations and allowing intertwin transfer of volume, red blood cells, vasoactive substances, and hormones. Three principal types of these anastomoses exist, with either unidirectional or bidirectional flow. Unidirectional flow occurs from the arterial to the venous side across arteriovenous (A-V) anastomoses, existing in both directions (A-V for donor to recipient and V-A for recipient to donor). A-V anastomoses end in a shared cotyledon where the arterial villous circulation of one twin links to the venous villous return of the other
at the level of the intervillous space. Artery-to-artery (A-A) and vein-to-vein (V-V) anastomoses are thought to remain after villous involution. Accordingly, their connections are superficial and allow bidirectional blood flow, as there is no interposed villous vascular tree. The overall direction and magnitude of volume shift from twin to twin is determined by the types of connection, vessel calibers, and the pulse pressure in each vascular compartment, while the location of shared cotyledons defines the vascular equator and the division of placental territory for each twin. TTTS results from progressive unbalanced chronic perfusion of blood components from donor to recipient twin across placental anastomoses. Such unbalanced transfer is more likely in those MC placentas with a preponderance of unidirectional A-V anastomoses, coupled with a lack of superficial balancing A-A or V-V anastomoses, or when these bidirectional anastomoses are unusually small.6 In addition, small caliber deep capillary anastomoses may allow the transfer of vasoactive mediators, despite their lack of contribution to the volume imbalance of TTTS.7
Clinical Manifestations of TTTS The principal clinical feature of TTTS is evidence of hypervolemia in the recipient twin with concurrent evidence of hypovolemia in the donor twin, which may be further complicated by secondary cardiovascular abnormalities. Today, prenatal ultrasound allows for the accurate diagnosis of TTTS and staging of its severity. It is important to consider that the signs of hyper- and hypovolemia evolve during gestation, and accordingly the clinical picture may vary in the first and second trimesters.
Fig. 1 The angioarchitecture of the monochorionic placenta determines the type of complications that occur, as well as the method of treatment.
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In the first trimester, fetal urination only provides a small contribution to amniotic fluid (AF) volume. Accordingly, polyhydramnios and oligohydramnios are not as prominent as later in gestation. During a first trimester ultrasound, discordance of nuchal translucency thickness as well as ductus venosus and tricuspid valve flow abnormalities may be the only signs of volume imbalance, and are related to the clinical progression to TTTS with AF and growth discordance later in the second trimester.8 In the second trimester, the sequence of recipient polyuria and donor oliguria, with the associated finding of the twin polyhydramnios/oligohydramnios sequence, becomes the lead diagnostic criterion for TTTS (►Fig. 2). Once this diagnostic threshold has been reached, the obstetrical impact of accelerating polyhydramnios and the fetal cardiovascular manifestations define the risks for preterm birth, fetal endorgan damage and stillbirth, respectively. As TTTS evolves, the donor twin responds to the decreasing blood volume and renal perfusion by a compensatory increase in the activity of the renin-angiotensin system (RAS), producing vasoconstriction, oliguria, and oligohydramnios. Renal hypoperfusion results in renal tubular hypoplasia and atrophy. Decreased bladder distension occurs, with decreased frequency of bladder emptying, or complete absence of bladder filling in a 60-minute period. These findings may progress to oligohydramnios (less than a 2 cm maximal vertical fluid pocket [MVP]) or anhydramnios
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—often noted as a “stuck twin.” Abnormal umbilical artery findings, such as absent end-diastolic velocity, may also occur when placental share is unequal in the presence of TTTS (►Fig. 2). The recipient twin responds to hypervolemia by releasing atrial natriuretic peptide as a result of atrial distension. This increases urination with resulting polyhydramnios. Fetal natriuretic peptide and brain natriuretic peptide, both diuretics and potent vasodilators, promote polyuria and have been shown to be higher in the recipient twin, correlating with cardiac dysfunction.9 Despite a down regulation of renal RAS in response to hypervolemia, overall recipient renin levels are paradoxically elevated, postulated to result principally from recipient placental up-regulation, and potentially some local transfer across vascular connections from the donor, predisposing to cardiomyopathy and hypertension.10 Recipient hypervolemia and polyuria may be detected by ultrasound as bladder distension, failure of complete bladder emptying, and increasing AF volumes. Cardiovascular manifestations of TTTS result from the combination of intravascular volume changes and exposure to vasoactive mediators. The recipient fetus bears increased risk for myocardial dysfunction, including myocardial hypertrophy from volume overload and functional right outflow obstruction. Ultrasound may detect an increase in cardiac size, increased cardiothoracic ratio, and depressed myocardial performance index (►Fig. 3).
Fig. 2 Ultrasound findings representing staging for TTTS with the Quintero et al method. 21 The twin polyhydramnios and oligohydramnios sequence is the lead diagnostic criterion for TTTS, Stage I, while the absence of bladder filling for the donor is a criteria for Stage II TTTS. Critically abnormal Doppler findings are noted for Stage III, and fetal hydrops for Stage IV. TTTS, twin-to-twin transfusion syndrome. American Journal of Perinatology
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Fig. 3 Recipient cardiovascular manifestations of TTTS. Exam findings from a case under surveillance with development of TTTS at 26 weeks gestation. Panels A to C demonstrate recipient twin MPI progressively increased during course of surveillance and progression to TTTS, Stage IV. The MPI reflects global myocardial function, and may be calculated as the sum of isovolumetric contraction and relaxation times divided by the ejection time, and normal left ventricular MPI values are typically less than 0.45. 48 Panels E and F demonstrate abnormal Doppler findings for the recipient diagnosed with TTTS at 26 weeks gestation, with (E) umbilical vein pulsations and (F) reversal of the atrial wave of the ductus venosus. MPI, myocardial performance index; TTTS, twin-to-twin transfusion syndrome.
Cardiac dysfunction may also appear on fetal examinations as atrioventricular regurgitation, reversal of transverse arch blood flow direction, and fusion of the early-active phase waveforms of the atrioventricular inflow pattern (diastolic dysfunction). Subsequent possible increases in the Doppler indices of the ductus venous and the occurrence of umbilical venous pulsations have been associated with development of hydrops in the recipient twin. A paradoxical decrease in recipient fetal urination and AF levels may be caused by progressive decreased forward flow in a recipient if cardiac function deteriorates. Cardiovascular signs of TTTS can manifest independent of volume abnormalities.11 In the third trimester, fetal discordance of growth and fluid may occur, and uterine activity may further impact on placental dynamics. Maternal symptoms may also be present as polyhydramnios, may increase uterine distension, shorten cervical length, and lead to preterm labor. In addition, clinicians need to be aware of the potential for maternal mirror syndrome, a rare condition featuring maternal edema in association with fetal hydrops, and a serious risk to maternal and fetal morbidity.12 Maternal symptoms such as rapid onset of edema with respiratory or cardiac compromise should prompt assessment for fetal signs of TTTS. There is also a form of acute peripartum TTTS, featuring a hemoglobin discordance of > 8 g/dL without reticulocytosis American Journal of Perinatology
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or hypovolemic shock, which has been described to occur in 2.5% of MC twin gestations and occurs more often in association with vaginal delivery and first order twin birth.13 This form of TTTS represents the neonatal diagnosis for this condition that was widely used before the development of prenatal diagnostic criteria.
Clinical Surveillance and Diagnostic Criteria for TTTS All twin pregnancies are considered “at risk” until placentation is determined. Assignment of chorionicity is accurately achievable in the first trimester. Among MC gestations, increased surveillance is recommended, given that the onset and progression of TTTS are variable, and early diagnosis with prompt treatment prolongs gestational age and improves survival rates. The diagnosis of TTTS is based on the detection of polyhydramnios/oligohydramnios sequence in a MC twin pair. Strict criteria are important to distinguish TTTS from AF discordance, or sIUGR. The U.S. definition of polyhydramnios in the recipient is an MVP of 8 cm or more. The European definition uses an MVP of greater than 10 cm after 20 weeks gestation. Oligohydramnios in the donor is noted when the MVP is less than 2 cm. Discordant fetal bladders with
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markedly enlarged bladder in the recipient and a small bladder in the donor during most of the examination may also be observed (►Figs. 2 and 3). Biweekly ultrasound assessments starting at 16 weeks gestation are recommended for MC gestations to detection and subsequently stage TTTS. These examinations include twin maximal vertical AF pockets, assessment of fetal growth, and bladder size.1 Weekly assessment is recommended if clinical suspicion for progression to TTTS is increased, such as with AF discordance.1 A Doppler profile for each fetus and a maternal cervical length measurement complete the staging assessment and assist with management decisions once TTTS is detected. Doppler profiles for both fetuses should include umbilical artery, ductus venosus, and umbilical vein Doppler as these parameters define the severity of TTTS. In addition, middle cerebral artery peak systolic velocity (MCA-PSV) measurements are necessary to diagnose or distinguish between coexisting TAPS (►Fig. 4). In the absence of diagnostic signs, prediction of which MC gestation will develop TTTS is limited and requires ongoing ultrasound surveillance until delivery to detect late onset complications, although ultrasound parameters and biomarkers are being investigated for this purpose. Findings indicating increased risk for progression to TTTS include NT discordance with abnormal ductus venosus flow,8 AF discordance and/or fetal growth discordance of 25% or more,14 intertwin abdominal circumference difference > 10% between 14 and 22 weeks gestation,15 and certain cardiac parameters.11
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Surveillance of MC twins must also account for the potential for twin anemia, TAPS, which complicates up to 5% of MC pregnancies as a spontaneous occurrence. TAPS can also complicate true TTTS and also affects up to 13% of TTTS MC pregnancies after laser therapy.16 TAPS is diagnosed prenatally with the use of Doppler measurements of the MCA-PSV. TAPS is diagnosed if MCA-PSV greater than 1.5 MoM is observed in the setting of a cotwin with MCA-PSV less than 1.0 MoM, absent findings of TTTS, such as fluid volume imbalance.16 Although fetal size discrepancy is not required for the diagnosis of TTTS, fetal growth assessments are integral to effective serial surveillance because unequal placental sharing in MC twins may lead to isolated discordant growth, defined as an intertwin size difference of 25%. Up to 20% of pregnancies complicated by growth discordance subsequently develop TTTS, and 30% of pregnancies with late onset growth discordance are at risk for significant hemoglobin discordance developing in the setting of equal placental share but small unidirectional anastomoses.17 sIUGR indicates that the estimated fetal weight of the smaller twin falls below the 10th percentile. AF discordance may also occur, although there is the absence of polyhydramnios in the normally grown twin. Three patterns of sIUGR have been described based on placental share and umbilical artery flow patterns, with variable rates of unanticipated stillbirth as high as 15%.18 A discussion of sIUGR is beyond the scope of this article, although it is important to consider this diagnosis in the surveillance of MC pregnancies, particularly since it may occur following the treatment of TTTS.
Fig. 4 Clinical management schematic for MC gestations with timing of typical surveillance methods and potential complications. MC, monochorionic. American Journal of Perinatology
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Twin-to-Twin Transfusion Syndrome
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As MC gestations are also at increased risk for aneuploidy and congenital anomalies, patients should receive genetic counseling and second trimester detailed fetal anatomical assessments including fetal echocardiography. Genotypic and phenotypic discordances in MC twins are related to complex and dynamic interactions between genetic, epigenetic, and environmental factors.19 Overall, concordant congenital abnormalities are found in 10% of all MC twins, while an additional 6% of MC twins can exhibit discordance for structural anomalies.19 Cardiac defects are most frequent, however, abnormalities of the central nervous system, as well as cloacal and urogenital anomalies can occur. Discordance of fetal brain abnormalities may also occur in the setting of severe TTTS, sIUGR, and in cases of single twin demise (►Fig. 5). Abnormal brain findings may evolve to include ventriculomegaly, arrest of head growth, or frank hydrancephaly. Such cases may also arise following laser surgery, where acute changes related to vascular reperfusion injury may occur. On the maternal side, the surveillance of the MC twin gestation includes symptom assessment related to polyhydramnios along with ultrasound examination of cervical length due to an increased risk for preterm birth above the background incidence. The risk for preterm birth correlates independently with shortened cervical length in TTTS cases,20 and gestational age at delivery is the strongest predictor of outcome.
Prognostic Assessment of TTTS Disease Severity Quintero et al developed the current commonly used staging system for TTTS by describing sonographic and clinical parameters to delineate a sequence of events representing disease progression.21 Stage I is diagnosed when the diagnostic criteria of fluid imbalance are met, the bladder remains visible in the donor, and normal Doppler findings are observed. In Stage II, the bladder is no longer visible in the donor, and Stage III is noted when a critically abnormal Doppler in either twin is observed, including absent-reverse diastolic flow in the donor or recipient umbilical artery,
absent/reverse flow in the ductus venosus, or pulsatile flow in the umbilical vein. Stage IV is defined as the presence of hydrops is present in either fetus, while Stage V indicates the demise of one or both twins. Among patients referred for fetal therapy for suspected TTTS, 59% were referred after 20 weeks gestation, and the distribution of stages at the time of diagnosis following referral was as follows: Quintero et al Stage I in 28 (11%), Stage II in 50 (20%), Stage III in 150 (60%), Stage IV in 15 (6%), and Stage V in 6 (2%).22 This pattern demonstrates the need for improved early surveillance with the goal of achieving earlier referral.22 Staging of TTTS with the goal of predicting disease severity and prognosis is challenging due to the variation in presenting features, lack of predictable disease progression, and the potential for different disease impact on recipient and donor. Survival outcomes based on stage have been supported by observational studies, although most recent studies show similar outcomes across all stages treated with laser surgery.23 Alternate staging systems incorporating cardiac function parameters have been proposed.11 Although such assessments provide information about the natural history of TTTS, given the reversible nature of the cardiac findings, there is currently insufficient evidence to prove their clinical value in predicting fetal survival postlaser treatment. Currently, the prediction of improved survival at earlier Quintero et al stages is not significantly enhanced by more elaborate staging systems and accordingly, these have not replaced the original method described by Quintero et al. Placental share and velamentous cord insertion (VCI) affect the outcome of MC pregnancies and TTTS, although these factors are not causative of TTTS. The severity of birthweight discordance correlates with unequal placental share and VCI, and may also vary based on types of anastomoses present and the potential for nutrient exchange between the fetuses with differing placental shares.24 The presence of a VCI correlates with increased the risk of small for gestational age (SGA), severe birthweight discordance, intrauterine fetal demise (IUFD), and lower gestational age at birth, for MC twin gestations both with and without TTTS.24 Donor survival rates following laser surgery are worsened with abnormally small placental share, and among TTTS cases, VCI occurs more often in the donor.24 Therefore, the presence of VCI may be a useful prognostic indicator in MC twins and TTTS cases postlaser treatment. In addition, the first trimester detection of VCI is possible, allowing for increased surveillance.24 MCA Doppler has emerged as an important component of the surveillance and staging examination for TTTS. Its diagnostic accuracy in the identification of TAPS in complex TTTS cases and after laser therapy is well established. The presence of elevated MCA-PSV in the recipient preoperatively is associated with increased risk for IUFD, although this finding is only noted in only 3% of TTTS recipients at diagnosis.25
Management of TTTS Fig. 5 Evidence of fetal brain injury, with cortical mantle thinning and ventriculomegaly noted bilaterally, occurring following demise of a cotwin in a monochorionic gestation. American Journal of Perinatology
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Untreated TTTS presenting in the second trimester has a perinatal mortality rate of almost 90%.26 Clinical
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management options for established TTTS include fetoscopic laser surgery, amnioreduction, selective reduction, or pregnancy termination. Factors determining the management approach include gestational age at diagnosis, cervical length, and technical factors impacting fetoscopy, such as placental location, cord insertion sites, and maternal anatomy. For Stage I TTTS, treatment remains an area of clinical equipoise, and a randomized trial is currently underway, comparing conservative management and primary laser therapy (ClinicalTrials.gov: NCT01220011). Until the results of this trial are reported, patients at Stage I can be offered fetoscopic laser or conservative management. An estimated 10% of patients with Stage I will show progression.27 These patients and those with Stage I disease with polyhydramniosrelated symptoms or cervical shortening are candidates for laser therapy. For Stages II to IV diagnosed between 16 and 26 weeks gestation, fetoscopic laser photocoagulation of placental anastomoses is the primary treatment.28 Clinical evidence supports, in selected cases, offering laser outside of these gestational ages with similar beneficial results,29 which requires special exemption by the Food and Drug Administration due to regulations regarding the use of fetoscopes in the United States. The laser procedure begins with the introduction of a fetoscope into the recipient’s sac to identify and coagulate all intertwin anastomoses present along the vascular equator with a laser fiber (Nd:YAG or diode). The proce-
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dure includes amnioreduction before the removal of the fetoscope. Innovation of techniques in fetoscopic laser photocoagulation has occurred with increasing experience and improved understanding of the angioarchitecture of the MC placenta (►Fig. 6). The nonselective laser occlusion of vessels initially described30 has been replaced by techniques selectively targeting the anastomotic vessels in a sequential fashion (sequential selective laser photocoagulation of communicating vessels).31 A recent advance targets the entire vascular equator with a “Solomon” technique to dichorionize the placenta.32 Evidence for improved outcomes with these techniques have been reported,31,32 while the use of equatorial laser dichorionization is currently being investigated in a clinical randomized trial (www.trialregister.nl, NTR 1245). When technically achieved, equatorial dichorionization converts the MC circulation into two independent vascular systems, reversing the hemodynamic disturbances associated with TTTS in the days following treatment. This also reduces the risk to the cotwin in the event of a single demise, and can reduce the recurrence of TTTS and the occurrence of TAPS postlaser, without increasing adverse outcomes32 (►Fig. 7). There are no formal contraindications to laser therapy, although a short cervical length (less than 15 mm) may indicate a higher risk of preterm delivery and may require consideration for a cervical cerclage.33 Laser surgery should also be offered before amnioreduction, which may be
Fig. 6 Schematic representation of laser techniques in the treatment of TTTS. The nonselective method initially described occludes all vessels crossing the intertwin membrane. 30 Selective laser ablation of placental anastomoses (X only) shifts the technique to occlude anastomoses where they occur, which thereby define the vascular equator, or shared zone of the placenta. The sequential selective laser photocoagulation of communicating vessels, not depicted, ablates the donor A-V first, to allow for hemodynamic improvement in volume status for the donor. 31 The equatorial laser dichorionization technique then further separates the fetal circulations by applying laser along chorionic plate in a virtual line connecting the ablated anastomoses, the vascular equator32 (shaded areas). A-V, arteriovenous; TTTS, twin-to-twin transfusion syndrome. American Journal of Perinatology
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Fig. 7 Fetoscopic laser photocoagulation of placental anastomoses with equatorial dichorionization. Panel A includes a V-V anastomosis between donor and recipient. Panel B includes the laser fiber in view, in preparation for selective ablation in panel C. Panel D shows the ablation of the intertwin vascular equator on the right side of the image. V-V, vein-to-vein.
associated with complications such as rupture of membranes and inadvertent septostomy and may decrease visibility due to intra-amniotic bleeding. These complications can reduce the success of the fetoscopic approach. As a second-line therapy, serial amniodrainage may be considered where laser treatment is not possible due to technical or regulatory restrictions. Amnioreduction is proposed to prolong pregnancy by reducing the risks of polyhydramnios, decreasing maternal discomfort, and reducing transplacental pressure on the fetal circulation. Selective feticide remains an important technique and management option in certain cases, such as with discordance for malformations or cerebral injury. Laser photocoagulation of the umbilical cord is the technique most often used. Selective feticide should not be considered a first-line therapy for TTTS given the improvements in outcome that have been realized with laser treatment. Nondirective counseling offering the option for selective feticide and pregnancy termination is a component of complete care, particularly given the unpredictability of neurodevelopmental outcome in the setting of unanticipated stillbirth or when TTTS complicates higher order multiples. For Stage V patients, with the death of one MC twin, outcomes for the surviving cotwin include a 12% risk for subsequent demise, an 18% risk for neurological abnormality, and a 68% risk of preterm birth.34 Evaluation of the surviving twin includes imaging of the fetal brain (ultrasound and magnetic resonance imaging [MRI]), and MCA Doppler to assess for anemia. In acute settings, fetal transfusion may be offered if evidence of fetal anemia is noted on MCA Doppler within the first 24 to 48 hours of the event; however, improvement in intact survival is unproven with this approach.35 A retrospective study of brain injury following MC American Journal of Perinatology
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cotwin demise demonstrated that most of the cases of abnormal brain findings on ultrasound were identified only after 1 to 2 weeks had passed, suggesting the importance of continued follow-up and serial imaging.36 MRI, particularly diffusion-weighted sequence MRI, has shown promise in detecting earlier changes suggestive of fetal brain injury,37 although it remains to be determined if these findings consistently correlate with long-term outcome. Evidence of fetal brain injury on ultrasound is correlated with poor prognosis, whereas absence of abnormal imaging findings is promising36; however, cautious counseling is warranted given that it cannot assure normal long-term neurodevelopmental outcome. Multiple assessments and decision points may occur in the course of TTTS management, utilizing information from diagnostic and staging examinations, fetoscopy, and postlaser ultrasound surveillance. Fetoscopic assessment of the quality of laser procedure and placental share may aid in predicting disease progression or complications. In addition, ultrasound findings posttreatment assist in documenting resolution of the condition and also assess for risk factors that may impact eventual outcome. These include a shortened cervical length, IUGR, cerebral abnormalities, recurrence of TTTS, TAPS, or fetal demise. Though our ability to predict the risk of fetal demise following treatment is limited, preoperative and perioperative methods of evaluating risk have been reported.25 Clinical findings and patient counseling determine the best location for follow-up, the need for referral to a fetal medicine center, and the frequency of examinations. The specialist center provides comprehensive patient education on the condition, potential outcomes, and treatment options, while customizing support for patient-specific cultural factors of risk aversion and acceptance of medical counseling.
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Delivery management of twin-to-twin transfusion remains guided by retrospective study, and case-by-case details often determine a course of action. Stillbirth risk is increased among MC gestations,38 particularly for those affected by TTTS, and delivery is recommended by 34 to 36 weeks gestation, typically by cesarean section.
Outcomes with Treatment of TTTS Outcomes with treatment of TTTS reflect maternal and fetal characteristics at the time of diagnosis, as well as the mode of therapy. Treatment complications, gestational age at delivery, survival rates for one or both twins, and rate of short- and long-term morbidity among survivors are important outcome parameters for patient counseling. Survival at 6 months of life for at least one twin ranges from 76 to 88% following laser treatment for TTTS.28,32 Stagebased reports of outcomes for TTTS suggest similar results with treatment for laser, regardless of stage at diagnosis.23,39 The probability of two survivors at 6 months of life following laser treatment differs across studies based on methodology, ranging from 36 to 68%.28,32 The reported incidence of severe neurodevelopmental impairment at 2 to 5 years of age is 13 to 18%, with a cerebral palsy rate of 6 to 7%.40,41 Potential complications after laser include intrauterine fetal death of either fetus (13–30%) and preterm rupture of membranes (10%).28 Persistence of overt TTTS due to anastomoses missed during surgery (2–14%) and TAPS (2–13%) can also occur. The frequency of these complications depends on the ability to complete the ablation of anastomoses and the equator, which can vary due to placental location and operator experience. Repeat fetoscopic laser procedures may be required where progression of TTTS or TAPS occurs. In contrast, serial amniodrainage for the treatment of severe TTTS before 26 weeks’ gestation has a reported survival rate of 51 to 60% for at least one fetus28 and a rate of neurological handicap of 29%.42 Amniodrainage is also associated with significant risks including septostomy and rupture of membranes.43 Gestational age at delivery for TTTS patients following laser treatment has been consistently reported to be near a median of 32 to 33 weeks gestation (excluding higher order multiples), with improvement demonstrated as laser techniques and operator experience evolve.28,32,39 Results with serial amnioreduction reveal an earlier average gestational age at delivery of 29 weeks.28 For survivors of TTTS, structural heart disease is more prevalent, and among TTTS pairs, 11 to 13% of recipients have congenital heart disease.44 For recipients, chronic right-sided volume overload and vasoactive mediators may contribute to muscular hypertrophy and reduced anterograde flow in the right ventricular outflow tract. This may lead to the development of pulmonary stenosis.44 Although laser may address the cardiac changes directly by reducing volume overload in the recipient, amnioreduction does not improve the cardiac dysfunction, which may progress until delivery. However, recipient pulmonary stenosis occurs after both types of
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therapy, indicating a potential role for early imprinting, which may require novel approaches to address. The prospect for normal neurodevelopmental outcome among offspring of a TTTS pregnancy is an essential component of patient counseling and treatment selection. Although perinatal outcomes are improved with laser versus amnioreduction, less evidence exists regarding long-term neurodevelopmental outcomes.45 Level I evidence in support of laser over amnioreduction is lacking and the window for obtaining such research has passed, given the preponderance of evidence showing the survival benefit to laser. The latest Cochrane review meta-analysis published in 2008 concluded that laser results in a decreased mortality of both infants per pregnancy (relative risk [RR], 0.49; 95% confidence interval [CI], 0.30–0.79, one trial), less perinatal death (RR, 0.59; 95% CI, 0.0.40–0.87 adjusted for cluster, one trial) and less neonatal death (RR, 0.29; 95% CI, 0.14–0.61).45 The study reported no difference in rates of neurological abnormality in survivors at 6 months of age between the laser and amnioreduction groups. van Klink et al also performed a systematic review directly comparing amnioreduction with laser surgery on rates of severe cerebral injury and neurodevelopmental impairment in TTTS.46 The five studies included in the analysis (three comparative studies plus two follow-up studies from the Eurofetus trial) revealed an odds ratio of 7.69 (95% CI, 2.7– 20) for severe cerebral injury to occur in survivors of TTTS postamnioreduction versus laser. In the postlaser therapy group, the percentage of survivors with cerebral injury ranged from 0 to 7%, the risk for cerebral palsy at 6 years of age was 13%, and the rate of developmental delay was 5.5%.28,47 The analysis concluded that amnioreduction is associated with an increased risk for cerebral injury compared with laser surgery, although insufficient data were available to assess long-term neurodevelopmental outcomes.46 Studies showing little or no benefit to laser treatment versus amnioreduction in long-term neurodevelopmental outcome have been based on treatment with selective laser ablation.40 The newest equatorial laser dichorionization technique provides enhanced benefit by addressing the vascular
Fig. 8 Comparison of reported survival rates following treatment for TTTS at 6 months of age. Both studies included all stages of TTTS. 28,32 TTTS, twin-to-twin transfusion syndrome. American Journal of Perinatology
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anastomoses causing TTTS in addition to the vascular equator. This shortens the exposure of the fetuses to the impact of TTTS, protects the survivor in event of cotwin demise, and prolongs the gestational age until delivery, which remains the most important predictor of neurological outcome. In addition, when compared with prior published outcomes, the equatorial technique has provided outcomes with improved survivor rates (►Fig. 8). Unfortunately, no pregnancy is without a baseline risk for preterm birth or developmental delay, and the risk is highest in MC twin as compared with singletons or dichorionic gestations. A prospective study of a cohort of 136 pairs of MC twins that were followed up from the first trimester until 2 years of age revealed a rate of 10% for neurodevelopmental impairment alone and a rate of a composite outcome of 22% for death or impairment.41 The risks of death and impairment were increased with TTTS and assisted conception. The rate of cerebral palsy was 2%, 10-fold higher than background rates. TTTS accounted for one in five infants with impairment and for the majority of infants with cerebral palsy in the cohort. TTTS may reverse once successfully treated, with no longterm impact on survivors independent of gestational age. In general, regardless of the treatment approach for TTTS, the increased risks of preterm birth and antenatal brain injury, caused by the disease or the reperfusion associated with laser, necessitate cranial ultrasound examination after birth and routine neurodevelopmental follow-up.41
Conclusion
7 van den Wijngaard JP, Lopriore E, van der Salm SM, et al. Deep-
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TTTS is a complication of MC placentation with a well-developed clinical screening, detection, and treatment paradigm that improves outcomes. Advances in the management of TTTS, resulting through the cooperative work of international teams of investigators, serve as an important example of progress in perinatal medicine, and provide hope for the future. Given the current limitations in ability to predict the onset of the condition, and the challenge to improve both short and long outcomes with treatment, continued investigation is paramount.
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Twin-to-Twin Transfusion. Twin-to-twin transfusion syndrome (TTTS). J Perinat Med 2011;39(2):107–112 Blickstein I. Monochorionicity in perspective. Ultrasound Obstet Gynecol 2006;27(3):235–238 Martin J, Hamilton B, Osterman M, Curtin S, Mathews TJ. Births: final data for 2012. Natl Vital Stat Rep 2013;62(9):1–27 Kulkarni AD, Jamieson DJ, Jones HW Jr, et al. Fertility treatments and multiple births in the United States. N Engl J Med 2013; 369(23):2218–2225 Knopman J, Krey LC, Lee J, Fino ME, Novetsky AP, Noyes N. Monozygotic twinning: an eight-year experience at a large IVF center. Fertil Steril 2010;94(2):502–510 De Paepe ME, Shapiro S, Greco D, et al. Placental markers of twinto-twin transfusion syndrome in diamniotic-monochorionic twins: A morphometric analysis of deep artery-to-vein anastomoses. Placenta 2010;31(4):269–276
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hidden anastomoses in monochorionic twin placentae are harmless. Prenat Diagn 2007;27(3):233–239 Matias A, Montenegro N, Loureiro T, et al. Screening for twin-twin transfusion syndrome at 11-14 weeks of pregnancy: the key role of ductus venosus blood flow assessment. Ultrasound Obstet Gynecol 2010;35(2):142–148 Bajoria R, Ward S, Chatterjee R. Natriuretic peptides in the pathogenesis of cardiac dysfunction in the recipient fetus of twin-twin transfusion syndrome. Am J Obstet Gynecol 2002; 186(1):121–127 Galea P, Barigye O, Wee L, Jain V, Sullivan M, Fisk NM. The placenta contributes to activation of the renin angiotensin system in twin-twin transfusion syndrome. Placenta 2008; 29(8):734–742 Rychik J, Tian Z, Bebbington M, et al. The twin-twin transfusion syndrome: spectrum of cardiovascular abnormality and development of a cardiovascular score to assess severity of disease. Am J Obstet Gynecol 2007;197(4):e1–e8 Braun T, Brauer M, Fuchs I, et al. Mirror syndrome: a systematic review of fetal associated conditions, maternal presentation and perinatal outcome. Fetal Diagn Ther 2010;27(4):191–203 Lopriore E, Holtkamp N, Sueters M, Middeldorp J, Walther F, Oepkes D. Acute peripartum twin-twin transfusion syndrome: Incidence, risk factors, placental characteristics and neonatal outcome. J Obstet Gynaecol Res 2014;40(1):18–24 Carver A, Haeri S, Moldenhauer J, Wolfe HM, Goodnight W. Monochorionic diamniotic twin pregnancy: timing and duration of sonographic surveillance for detection of twin-twin transfusion syndrome. J Ultrasound Med 2011;30(3):297–301 O’Connor C, McAuliffe FM, Breathnach FM, et al; Perinatal Ireland Research Consortium. Prediction of outcome in twin pregnancy with first and early second trimester ultrasound. J Matern Fetal Neonatal Med 2013;26(10):1030–1035 Slaghekke F, Kist WJ, Oepkes D, et al. Twin anemia-polycythemia sequence: diagnostic criteria, classification, perinatal management and outcome. Fetal Diagn Ther 2010;27(4):181–190 Lewi L, Gucciardo L, Huber A, et al. Clinical outcome and placental characteristics of monochorionic diamniotic twin pairs with earlyand late-onset discordant growth. Am J Obstet Gynecol 2008; 199(5):e1–e7 Gratacós E, Lewi L, Muñoz B, et al. A classification system for selective intrauterine growth restriction in monochorionic pregnancies according to umbilical artery Doppler flow in the smaller twin. Ultrasound Obstet Gynecol 2007;30(1):28–34 Cao AMG. Phenotypic and genotypic discordance in monozygotic twins. In: Blickstein I, Keith LG, eds. Multiple Pregnancy: Epidemiology, Gestatio, and Perinatal Outcome. UK: Taylor & Francis; 2005:226–232 Robyr R, Boulvain M, Lewi L, et al. Cervical length as a prognostic factor for preterm delivery in twin-to-twin transfusion syndrome treated by fetoscopic laser coagulation of chorionic plate anastomoses. Ultrasound Obstet Gynecol 2005;25(1):37–41 Quintero RA, Morales WJ, Allen MH, Bornick PW, Johnson PK, Kruger M. Staging of twin-twin transfusion syndrome. J Perinatol 1999;19(8 Pt 1):550–555 Gandhi M, Papanna R, Teach M, Johnson A, Moise KJ Jr. Suspected twin-twin transfusion syndrome: how often is the diagnosis correct and referral timely? J Ultrasound Med 2012;31(6): 941–945 Rossi AC, D’Addario V. The efficacy of Quintero staging system to assess severity of twin-twin transfusion syndrome treated with laser therapy: a systematic review with meta-analysis. Am J Perinatol 2009;26(7):537–544 Costa-Castro T, De Villiers S, Montenegro N, et al. Velamentous cord insertion in monochorionic twins with or without twin-twin transfusion syndrome: does it matter? Placenta 2013;34(11): 1053–1058
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individualized risk of early fetal death after laser therapy in twinto-twin transfusion syndrome. Prenat Diagn 2013:1–6 Urig MA, Clewell WH, Elliott JP. Twin-twin transfusion syndrome. Am J Obstet Gynecol 1990;163(5 Pt 1):1522–1526 Rossi AC, D’Addario V. Survival outcomes of twin-twin transfusion syndrome stage I: a systematic review of literature. Am J Perinatol 2013;30(1):5–10 Senat MV, Deprest J, Boulvain M, Paupe A, Winer N, Ville Y. Endoscopic laser surgery versus serial amnioreduction for severe twin-to-twin transfusion syndrome. N Engl J Med 2004;351(2): 136–144 Baud D, Windrim R, Keunen J, et al. Fetoscopic laser therapy for twin-twin transfusion syndrome before 17 and after 26 weeks’ gestation. Am J Obstet Gynecol 2013;208(3):e1–e7 De Lia JE, Cruikshank DP, Keye WR Jr. Fetoscopic neodymium:YAG laser occlusion of placental vessels in severe twin-twin transfusion syndrome. Obstet Gynecol 1990;75(6):1046–1053 Quintero RA, Ishii K, Chmait RH, Bornick PW, Allen MH, Kontopoulos EV. Sequential selective laser photocoagulation of communicating vessels in twin-twin transfusion syndrome. J Matern Fetal Neonatal Med 2007;20(10):763–768 Baschat AA, Barber J, Pedersen N, Turan OM, Harman CR. Outcome after fetoscopic selective laser ablation of placental anastomoses vs equatorial laser dichorionization for the treatment of twin-to-twin transfusion syndrome. Am J Obstet Gynecol 2013;209(3):e1–e8 Salomon LJ, Nasr B, Nizard J, et al. Emergency cerclage in cases of twin-to-twin transfusion syndrome with a short cervix at the time of surgery and relationship to perinatal outcome. Prenat Diagn 2008;28(13):1256–1261 Ong SS, Zamora J, Khan KS, Kilby MD. Prognosis for the co-twin following single-twin death: a systematic review. BJOG 2006; 113(9):992–998 Senat MV, Loizeau S, Couderc S, Bernard JP, Ville Y. The value of middle cerebral artery peak systolic velocity in the diagnosis of fetal anemia after intrauterine death of one monochorionic twin. Am J Obstet Gynecol 2003;189(5):1320–1324 Simonazzi G, Segata M, Ghi T, et al. Accurate neurosonographic prediction of brain injury in the surviving fetus after the death of a monochorionic cotwin. Ultrasound Obstet Gynecol 2006;27(5): 517–521 Weisz B, Hoffmann C, Ben-Baruch S, et al. Early detection of severe brain lesions after fetoscopic laser treatment in twin-twin transfusion syndrome by diffusion weighted sequence MRI (e-pub ahead of print). Ultrasound Obstet Gynecol 2013; doi: 10.1002/ uog.13283
delivery in monochorionic diamniotic twin pregnancies 32 weeks of gestation: a multicentre retrospective cohort study. BJOG 2011;118(9):1090–1097 Chmait RH, Kontopoulos EV, Korst LM, Llanes A, Petisco I, Quintero RA. Stage-based outcomes of 682 consecutive cases of twin-twin transfusion syndrome treated with laser surgery: the USFetus experience. Am J Obstet Gynecol 2011;204(5):e1–e6 Lenclen R, Ciarlo G, Paupe A, Bussieres L, Ville Y. Neurodevelopmental outcome at 2 years in children born preterm treated by amnioreduction or fetoscopic laser surgery for twin-to-twin transfusion syndrome: comparison with dichorionic twins. Am J Obstet Gynecol 2009;201(3):e1–e5 Ortibus E, Lopriore E, Deprest J, et al. The pregnancy and long-term neurodevelopmental outcome of monochorionic diamniotic twin gestations: a multicenter prospective cohort study from the first trimester onward. Am J Obstet Gynecol 2009;200(5):e1–e8 Rossi AC, D’Addario V. Laser therapy and serial amnioreduction as treatment for twin-twin transfusion syndrome: a metaanalysis and review of literature. Am J Obstet Gynecol 2008;198(2): 147–152 Mari G, Roberts A, Detti L, et al. Perinatal morbidity and mortality rates in severe twin-twin transfusion syndrome: results of the International Amnioreduction Registry. Am J Obstet Gynecol 2001; 185(3):708–715 Herberg U, Gross W, Bartmann P, Banek CS, Hecher K, Breuer J. Long term cardiac follow up of severe twin to twin transfusion syndrome after intrauterine laser coagulation. Heart 2006;92(1): 95–100 Roberts D, Gates S, Kilby M, Neilson JP. Interventions for twin-twin transfusion syndrome: a Cochrane review. Ultrasound Obstet Gynecol 2008;31(6):701–711 van Klink JM, Koopman HM, van Zwet EW, Oepkes D, Walther FJ, Lopriore E. Cerebral injury and neurodevelopmental impairment after amnioreduction versus laser surgery in twin-twin transfusion syndrome: a systematic review and meta-analysis. Fetal Diagn Ther 2013;33(2):81–89 Salomon LJ, Ortqvist L, Aegerter P, et al. Long-term developmental follow-up of infants who participated in a randomized clinical trial of amniocentesis vs laser photocoagulation for the treatment of twin-to-twin transfusion syndrome. Am J Obstet Gynecol 2010; 203(5):e1–e7 Hernandez-Andrade E, Figueroa-Diesel H, Kottman C, et al. Gestational-age-adjusted reference values for the modified myocardial performance index for evaluation of fetal left cardiac function. Ultrasound Obstet Gynecol 2007;29(3):321–325
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