Twin-to-twin transfusion syndrome
|Twin-to-twin transfusion syndrome|
|Classification and external resources|
A pair of newborn twins affected by TTTS. Both the recipient (left) and donor (right) survived.
|ICD-10||O43.0, P02.3, P50.3|
|ICD-9||762.3 , 772.0|
Twin-to-twin transfusion syndrome (TTTS, also known as Feto-Fetal Transfusion Syndrome (FFTS) and Twin Oligohydramnios-Polyhydramnios Sequence (TOPS)) is a complication of monochorionic diamniotic (MCDA) pregnancy in which the presence of oligohydramnios in one sac and polyhydramnios in the other sac resulting from intertwin vascular connections within the placenta. 
Twin-twin transfusion syndrome (TTTS) is diagnosed prenatally by ultrasound imaging. The diagnosis requires that certain symptoms be present in an identical twin, or higher-order multiple pregnancy in which 2 or more babies share a single placenta. They are, for the "Monochorionic-Diamniotic" pregnancies, with Individual Amnions: The presence of oligohydramnios (defined as a maximal vertical pocket [MVP] of <2 cm) in one sac, and of polyhydramnios (a MVP of >8 cm) in the other sac. MVP of 2 cm and 8 cm represent the 5th and 95th percentiles for amniotic fluid measurements, respectively, and the presence of both is used to define stage I TTTS. If there is a subjective difference in amniotic fluid in the 2 sacs that fails to meet these criteria, progression to TTTS occurs in <15% of cases. Although growth discordance (usually defined as >20%) and intrauterine growth restriction (IUGR) (estimated fetal weight <10% for gestational age) often complicate TTTS, growth discordance itself or IUGR itself are not diagnostic criteria. The differential diagnosis may include selective IUGR, or possibly an anomaly in 1 twin causing amniotic fluid abnormality. Twin anemia-polycythemia sequence (TAPS) has been recently described in MCDA gestations, and is defined as the presence of anemia in the donor and polycythemia in the recipient, diagnosed antenatally by middle cerebral artery (MCA)–peak systolic velocity (PSV) >1.5 multiples of median in the donor and MCA PSV <1.0 multiples of median in the recipient, in the absence of oligohydramnios-polyhydramnios. Further studies are required to determine the natural history and possible management of TAPS. TTTS can occur in a MCDA twin pair in triplet or higher-order pregnancies.
The most commonly used TTTS staging system was developed by Quintero et al. in 1999, and is based on sonographic findings. The TTTS Quintero staging system includes 5 stages, ranging from mild disease with isolated discordant amniotic fluid volume to severe disease with demise of one or both twins. This system has some prognostic significance and provides a method to compare outcome data using different therapeutic interventions. Although the stages do not correlate perfectly with perinatal survival, it is relatively straightforward to apply, may improve communication between patients and providers, and identifies the subset of cases most likely to benefit from treatment.
The Quintero staging of twin-twin transfusion syndrome 
|Stage||Ultrasound parameter||Categorical criteria|
|I||MVP of amniotic fluid||MVP <2 cm in donor sac; MVP >8 cm in recipient sac|
|II||Fetal bladder||Symptoms of Stage I except Donor has no measurable fluid, Nonvisualization of fetal bladder in donor twin over 60 min of observation|
|III||Symptoms of Stage II with Doppler anomalies in the Umbilical artery, ductus venosus, and umbilical vein||Absent or reversed umbilical artery diastolic flow, reversed ductus venosus a-wave flow, pulsatile umbilical vein flow|
|IV||Symptoms of Stage III with Fetal hydrops||Hydrops Fetalis in one or both twins|
|V||Single or Double Loss||Fetal demise of one or both twins|
MVP = maximal vertical pocket
Since the development of the Quintero staging system, much has been learned about the changes in fetal cardiovascular physiology that accompany disease progression (discussed below). Myocardial performance abnormalities have been described, particularly in recipient twins, including those with only stage I or II TTTS. Several groups of investigators have attempted to use assessment of fetal cardiac function to either modify the Quintero TTTS stage or develop a new scoring system. While this approach has some benefits, the models have not yet been prospectively validated. As a result, a recent expert panel concluded that there were insufficient data to recommend modifying the Quintero staging system or adopting a new system. Thus, despite debate over the merits of the Quintero system, at this time it appears to be a useful tool for the diagnosis of TTTS, as well as for describing its severity, in a standardized fashion.
There are several second- and even first-trimester sonographic findings that have been associated with TTTS.
- Crown-rump length discordance
- Nuchal translucency >95th percentile or discordance >20% between twins
- Reversal or absence of ductus venosus A-wave
- Abdominal circumference discordance
- Membrane folding
- Velamentous placental cord insertion (donor twin)
- Placental echogenicity (donor portion hyperechoic)
The presentation of TTTS is highly variable and often does not progress in a predictable manner. Single twin survival rates in TTTS vary widely between 15-70%, depending on gestational age at diagnosis and severity of disease. Two thirds of recipient twins show diastolic dysfunction, as indicated by a prolonged ventricular isovolumetric relaxation time, which is associated with an increased risk of fetal death. Scoring systems that include cardiac dysfunction have been developed, but their usefulness to predict outcome in TTTS remains controversial. The natural history of advanced (eg, stage >III) TTTS is bleak, with a reported perinatal loss rate of 70-100%, particularly when it presents <26 weeks. Even laser-treated TTTS is associated with a perinatal mortality rate of 30-50% (Table 7), and a 5-20% chance of long-term neurologic handicap (Table 8). Although the risk of membrane rupture may be as low as 10% in experienced centers, there remains a 10-30% procedure-associated fetal loss with laser.
Screening/Work-up: All women with a twin pregnancy should be offered an ultrasound examination at 10-13 weeks of gestation to assess viability, chorionicity, crown-rump length, and nuchal translucency. Serial sonographic evaluation should be considered for all twins with MCDA placentation, beginning at around 16 weeks and continuing about every 2 weeks until delivery. Screening for congenital heart disease is warranted in all monochorionic twins, in particular those complicated by TTTS.
Counseling: Extensive counseling should be provided to patients with pregnancies complicated by TTTS including natural history of the disease, as well as management options and their risks and benefits.
Stage I: The natural history of stage I TTTS is that more than three-fourths of cases remain stable or regress without invasive intervention, with perinatal survival of about 86%. Therefore, many patients with stage I TTTS may be managed expectantly. Stages I and II TTTS have been shown to regress following amnioreduction in up to 20-30% of cases, a rate that is not significantly different than with expectant management, especially for stage I.
Stages II, III, IV: Fetoscopic laser photocoagulation of placental anastemoses is considered by most experts to be the best available approach for states II, III, and IV TTTS in continuing pregnancies at < 26 weeks, but the meta-analysis data show no significant survival benefit, and the long-term neurologic outcomes in the Eurofetus trial were not different than in nonlaser-treated controls. Survival rates of 50-70% can be expected after fetoscopic laser for the treatment of TTTS (Table 7). Expectant management and amnioreduction remain 2 options in cases if TTTS > stage I at <26 weeks of gestation in which the patient does not have the ability to travel to a center that performs fetoscopic laser photocoagulation. In cases complicated by severe unequal placental sharing with marked discordant growth and IUGR, major malformation affecting 1 twin, or evidence of brain injury either before or subsequent to laser, selective reduction by cord occlusion or by termination of the entire pregnancy may be reasonable management choices for the patient and her family < 24 weeks’ gestation.
Stage V: In cases of death of 1 MCDA twin, the risks to the cotwin include a 10% risk of death and 10-30% risk of neurologic complications. No intervention has been evaluated in randomized trials to try to ameliorate outcome. Antepartum: Steroids for fetal maturation should be considered at 24 0/7 to 33 6/7 weeks, particularly in pregnancies complicated by stage > III TTTS, and those undergoing invasive interventions.
Delivery: Optimal timing of delivery for TTTS pregnancies depends on several factors, including disease stage and severity, progression, effect of interventions (if any), and results of antenatal testing. Timing of delivery at around 34-36 weeks may be reasonable in selected cases.
TTTS was first described by a German obstetrician, Friedrich Schatz, in 1875. Once defined by neonatal parameters—differences in birth weight and cord hemoglobin at the time of delivery—TTTS is now defined differently. Today, it is known that discordant fetal weights will most likely be a late manifestation, and fetal hemoglobin through cordocentesis is often equivalent in the twin pair even in severe TTTS.
TTTS in art
A painting known as the De Wikkellkinderen (The Swaddled Children), from 1617, is thought to represent a depiction of TTTS. The drawing shows twins that appear to be identical, but one is pale (possibly anemic), while the other is red (possibly polycythemic). Analysis of the family histories of the owners of the painting suggests that the twins did not survive to adulthood, although whether that is due to TTTS is uncertain.
Although somewhat of a stretch, due to the detail of "magical birthgiving" in the folklore, an example of TTTS might have been noted ages before Schatz classified it or the painting "De Wikkellkinderen" illustrated, as an old Norse fairy tale, "Tatterhood", seemed to explain it, with one of the two girls being lovely but weak (pale skin and delicacy of anemia has often associated with how girls were most expected to be at the time) and the other one, the title heroine, was considered hideous and too strong (polycythemia has a higher blood cell count and often includes unsightly blemishes). Of course, with both twins growing up to be healthy adults, the debate of truth in fiction is still a mystery.
- Twins and Multiple Births Association, Tamba
- The Twin to Twin Transfusion Syndrome Foundation
- Fetal Health Foundation
- Dr. Rubén Quintero at Jackson Memorial Hospital Miami, FL
- Texas Fetal Center (UTHealth Medical School and Children's Memorial Hermann Hospital) Twin to Twin Transfusion Syndrome
- The International Institute for the Treatment of TTTS
- Texas Children's Fetal Center, Twin-Twin Transfusion Syndrome
- TTTS Educational Video – Texas Children's Fetal Center
- Los Angeles Fetal Therapy, Children's Hospital Los Angeles - University of Southern California Fetal Therapy Program-TTTS
- The Center for Prenatal Pediatrics at Columbia University Medical Center- TTTS Evaluation & Laser Photocoagulation Therapy
- Twin-Twin Transfusion Syndrome – Children's Hospital Boston
- The Children's Hospital of Philadelphia
- The Brown Fetal Treatment Program – What is TTTS?
- Ohio State's Maternal Fetal Medicine
- St. Louis Fetal Care Institute TTTS Survivor Stories
- Skupski, Daniel W. MD, Twin-To-Twin Transfusion Syndrome, 2013. Jp Medical Ltd.
- Quintero, Ruben A. (editor), Twin-Twin Transfusion Syndrome, 2007. CRC Press
- Twin-twin transfusion syndrome. Society for Maternal-Fetal Medicine, Simpson LL. Am J Obstet Gynecol. 2013 Jan;208(1):3-18
- Simpson LL . Twin-twin transfusion syndrome . In: Copel JA editors. Obstetric imaging . 1st ed.. Philadelphia: Elsevier; 2012
- Quintero RA , Morales WJ , Allen MH , Bornick PW , Johnson PK , Kruger M . Staging of twin-twin transfusion syndrome . J Perinatol . 1999;19:550–555
- Huber A , Diehl W , Zikulnig L , Bregenzer T , Hackeloer BJ , Hecher K . Perinatal outcome in monochorionic twin pregnancies complicated by amniotic fluid discordance without severe twin-twin transfusion syndrome . Ultrasound Obstet Gynecol . 2006;27:48–52
- Danskin FH , Neilson JP . Twin-to-twin transfusion syndrome: what are appropriate diagnostic criteria? . Am J Obstet Gynecol . 1989;161:365–369
- Gandhi M , Papanna R , Teach M , Johnson A , Moise KJJ . Suspected twin-twin transfusion syndrome: how often is the diagnosis correct and referral timely? . J Ultrasound Med . 2012;31:941–945
- Slaghekke F , Kist WJ , Oepkes D , et al. Twin anemia-polycythemia sequence: diagnostic criteria, classification, perinatal management and outcome . Fetal Diagn Ther . 2010;27:181–190
- Taylor MJ , Govender L , Jolly M , Wee L , Fisk NM . Validation of the Quintero staging system for twin-twin transfusion syndrome . Obstet Gynecol . 2002;100:1257–1265
- Stamilio DM , Fraser WD , Moore TR . Twin-twin transfusion syndrome: an ethics-based and evidence-based argument for clinical research . Am J Obstet Gynecol . 2010;203:3–16
- 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;26:537–544
- Habli M , Michelfelder E , Cnota J , et al. Prevalence and progression of recipient-twin cardiomyopathy in early-stage twin-twin transfusion syndrome . Ultrasound Obstet Gynecol . 2012;39:63–68
- Michelfelder E , Gottliebson W , Border W , et al. Early manifestations and spectrum of recipient twin cardiomyopathy in twin-twin transfusion syndrome: relation to Quintero stage . Ultrasound Obstet Gynecol . 2007;30:965–971
- 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;197:392.e1–392.e8
- Lewi L , Jani J , Blickstein I , et al. The outcome of monochorionic diamniotic twin gestations in the era of invasive fetal therapy: a prospective cohort study . Am J Obstet Gynecol . 2008;199:514.e1–514.e8
- Acosta-Rojas R , Becker J , Munoz-Abellana B , et al. Twin chorionicity and the risk of adverse perinatal outcome . Int J Gynaecol Obstet . 2007;96:98–102
- Blickstein I . Monochorionicity in perspective . Ultrasound Obstet Gynecol . 2006;27:235–238
- Lewi L , Lewi P , Diemert A , et al. The role of ultrasound examination in the first trimester and at 16 weeks' gestation to predict fetal complications in monochorionic diamniotic twin pregnancies . Am J Obstet Gynecol . 2008;199:493.e1–493.e7
- . Sebire NJ , Souka A , Skentou H , Geerts L , Nicolaides KH . Early prediction of severe twin-to-twin transfusion syndrome . Hum Reprod . 2000;15:2008–2010
- Sebire NJ , D'Ercole C , Hughes K , Carvalho M , Nicolaides KH . Increased nuchal translucency thickness at 10-14 weeks of gestation as a predictor of severe twin-to-twin transfusion syndrome . Ultrasound Obstet Gynecol . 1997;10:86–89
- Kagan KO , Gazzoni A , Sepulveda-Gonzalez G , Sotiriadis A , Nicolaides KH . Discordance in nuchal translucency thickness in the prediction of severe twin-to-twin transfusion syndrome . Ultrasound Obstet Gynecol . 2007;29:527–532
- Linskens IH , de Mooij YM , Twisk JW , Kist WJ , Oepkes D , van Vugt JM . Discordance in nuchal translucency measurements in monochorionic diamniotic twins as predictor of twin-to-twin transfusion syndrome . Twin Res Hum Genet . 2009;12:605–610
- Maiz N , Staboulidou I , Leal AM , Minekawa R , Nicolaides KH . Ductus venosus Doppler at 11 to 13 weeks of gestation in the prediction of outcome in twin pregnancies . Obstet Gynecol . 2009;113:860–865
- 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;35:142–148
- De Paepe ME , Shapiro S , Greco D , et al. Placental markers of twin-to-twin transfusion syndrome in diamniotic-monochorionic twins: a morphometric analysis of deep artery-to-vein anastomoses . Placenta . 2010;31:269–276
- Kusanovic JP , Romero R , Gotsch F , et al. Discordant placental echogenicity: a novel sign of impaired placental perfusion in twin-twin transfusion syndrome? . J Matern Fetal Neonatal Med . 2010;23:103–106
- Johnson, A. & Moise, K., J. "Improving Survival in Twin-Twin Transfusion Syndrome. Contemporary OB/GYN December 2006" (PDF).
- Berger H, de Waard F, Molenaar Y (2000). "A case of twin-to-twin transfusion in 1617". Lancet 356 (9232): 847–8. doi:10.1016/S0140-6736(00)02665-9. PMID 11022944.
- Fox, Michael J. "Pg 197." Lucky man. New York: Hyperion, 2002.