Twin-Twin Transfusion Syndrome

TTTS is a rare condition that affects identical twin pregnancies, particularly those that share a monochorionic placenta.
The incidence of monochorionic twins is estimated to be around 0.3% to 0.4% of all pregnancies. However, it is important to note that these figures are general estimates, and the actual incidence may vary in different populations and regions. Additionally, advancements in assisted reproductive technologies (ART) have increased the likelihood of multiple pregnancies, including monochorionic twins. 
TTTS is one of the most common complications seen in monochorionic pregnancies, with a reported frequency of up to 15%. [1]

While the pathophysiology of TTTS is not fully understood, it is mainly related to the unbalanced vascular anastomosis on the placenta and release or suppression of vasoactive mediators [2,3] causing one fetus to be hypovolemic (donor) while the other is hypervolemic (recipient). This process results in oligohydramnios in the donor fetus and polyhydramnios in the recipient fetus representing the hallmark of TTTS diagnosis. Left untreated, severe TTTS prior to 24 weeks is associated with poor fetal survival rates. [4]  

Monochorionic twin gestation is considered a high risk pregnancy that require close monitoring to evaluate complications such as TTTS, selective fetal growth restriction (sFGR) or twin anemia polycythemia (TAPS). International guidelines recommend a first trimester ultrasound that is typically performed to confirm chorionicity and assess for any early signs of associated pathologies. This initial screening helps establish a baseline and identify any initial risk factors. Following the initial assessment, monochorionic twin pregnancies are often monitored more frequently than pregnancies with separate placentas. The exact frequency of ultrasounds may vary, but it is common for healthcare providers to recommend screenings every 2 weeks from the second trimester onwards. In addition to regular ultrasounds, Doppler flow studies may be performed during these screenings to assess blood flow characteristics in the umbilical cord and other fetal vessels. Abnormal flow patterns can indicate the development or progression of TTTS. [5]

Diagnosis of TTTS involves a combination of ultrasound imaging and Doppler flow studies. Ultrasound examination performed to determining monochorionicity is a prerequisite for TTTS. The presence and severity of TTTS is identified through signs such as discordant amniotic fluid levels, discordant bladder filling and abnormal Doppler blood flow characteristics in the umbilical artery and ductus venosus.
Several staging systems have been proposed to evaluate the severity of TTTS. Of these, the Quintero staging system [3] is most ubiquitously adopted and used to classify TTTS into stages based on severity. It provides a framework for assessing the condition based on specific ultrasound findings and helps guide treatment decisions and predict outcomes. The Quintero staging system consists of four stages, with each stage representing a progression in severity of TTTS:

Stage I:
The mildest form of TTTS. In this stage, ultrasound findings include discordance in amniotic fluid levels. Stage 1 is defined when a maximal vertical pocket (MVP) of above 8 cm is measured for the recipient twin and below 2 cm for the donor twin, The bladder of the donor twin is visible, indicating urine production.

Stage II:
Represents moderate TTTS. In this stage, there may be an increased discrepancy in amniotic fluid levels. Fetal bladder is not visualized in the donor twin, indicating that it is anuric.

Stage III:
Signifies advanced TTTS. In addition to the previous findings. One or both twins may exhibit signs of compromised fetal well-being, demonstrated abnormal Doppler flow patterns: umbilical artery absent or reversed end diastolic flow, ductus venosus absent or reversed a waves.

Stage IV:
Represents a critical form of TTTS. In this stage, in addition to the findings seen at stage 3, signs of severe cardiovascular compromise may be seen demonstrated by accumulation of fluid in two or more body compartments i.e. fetal hydrops. Doppler flow abnormalities are typically present, indicating significant circulatory imbalance.

Stage V:
This is the most severe form of TTTS. In this stage intrauterine demise of one or both twins have occurred due to the disease.
The Quintero staging system helps guide healthcare providers in determining appropriate management strategies for TTTS, ranging from conservative monitoring to various interventions.
It is important to note that the Quintero staging system provides a valuable framework but does not capture all aspects of the condition. Different groups have attempted to incorporate the wide spectrum of cardiac manifestations in the preoperative staging of the disease.  [6,7]
Changes in cardiac structure and function not reflected in Quintero staging occur in the recipient twin early in the evolution of TTTS. These include:  volume overload, ventricular dilatation and hypertrophy, atria ventricular regurgitation, right ventricular hypertrophy, pulmonary stenosis and diastolic dysfunction. [8,9]
Nonetheless, the lack of correlation between preoperative cardiac function and perinatal prognosis has hindered the development of their influence.[10] Each case of TTTS is unique, and additional social clinical factors, such as access to fetal centers, gestational age, maternal symptoms, and fetal echocardiography, are also considered in decision-making and prognosis.

Overall, the Quintero staging system offers a standardized approach to categorizing the severity of TTTS and assists in the management and communication of this complex condition.

In summary, the diagnosis of TTTS relies on a comprehensive ultrasound assessment and Doppler flow studies. The Quintero staging system facilitates classification. Challenges and limitations persist in diagnosing TTTS, necessitating ongoing research and refinement of diagnostic criteria. Improved diagnostic capabilities will enable timely intervention and optimize management for TTTS-affected pregnancies. Further advancements in diagnostic techniques are needed to enhance outcomes and ensure the best possible care for those with TTTS.

Overall prognosis depends on several factors including: TTTS stage, gestational age, additional co-morbidity such as sFGR and TAPS. While TTTS stage 1 can remain stable or resolve in up to 40 % of the cases [11], advanced stages (II-IV) managed expectantly, are expected to progress and associated with likelihood of intact co-twin survival is <10% [12]. With treatment prognosis differs significantly. Following fetoscopic laser pholocagulation of placental anastomosis, ~90% of the cases with present with at least 1 fetus alive at birth and ~70% with both fetuses alive at birth.

Expectant
Conservative management is an approach used in some cases of TTTS where the condition is diagnosed at a very early or late gestational age, when the severity does not warrant immediate intervention, when the patient opts against surgical treatment or when surgical treatment is not available. This management strategy involves close monitoring and observation without active medical or surgical intervention. Here are some key aspects of expectant management for TTTS:
Regular Monitoring: Expectant management typically involves ultrasound examinations that can be as frequent as daily evaluations to closely monitor the progress of the condition. This allows healthcare providers to assess the amniotic fluid levels, bladder visibility, Doppler flows as well as fetal growth, and overall well-being of the twins.
Maternal hydration and proper nutrition: Pregnant individuals may be advised to maintain adequate hydration and adequate diet.
Counseling and Support: Expectant management can be emotionally challenging for parents. Counseling and support from healthcare professionals in a multidisciplinary approach are crucial to address concerns, provide education, and ensure that the parents are well-informed and involved in decision-making.
It is important to note that expectant management is not suitable for all cases of TTTS and requires careful consideration of various factors, including the stage and severity of the condition, the gestational age, and the overall health of the twins. Individualized decision-making is crucial, and a healthcare team specializing in high-risk pregnancies, such as maternal-fetal medicine specialists, can guide parents in determining the most appropriate management approach for their specific case of TTTS.

Amnioreduction/Septostomy
Amnioreduction involves the removal of excess amniotic fluid from the amniotic sac of the recipient twin. Excess amniotic fluid or polyhydramnios, is a condition where there is an abnormal increase in the volume of amniotic fluid surrounding the recipient twin. This can cause maternal symptoms such as dyspnea, discomfort, and contractions.
The procedure is typically performed under ultrasound guidance, and a needle is inserted into the amniotic sac of the recipient twin. The amniotic fluid is then drained, usually in a controlled and gradual manner to avoid sudden changes and potential complications.
Amnioreduction can provide temporary relief of maternal symptoms and may be repeated if necessary. However, it is important to note that amnioreduction is considered a palliative measure and does not address the underlying cause of TTTS. For more definitive management, other interventions such as laser therapy or fetal surgery may be recommended, depending on the stage and severity of TTTS.
The specific decision to perform amnioreduction and the frequency of repetitive, serial  procedures is based on individual factors. Nowadays it is mainly indicated as a temporizing procedure in cases where laser ablation cannot be offered or performed or in advanced gestational ages with relatively mild disease. It is important to consult with a healthcare professional specializing in maternal-fetal medicine or TTTS management to determine the most appropriate treatment plan for a specific case of TTTS.
Septostomy involves creating a small opening or hole in the dividing membrane (septum) between the amniotic sacs of the twins. The purpose of septostomy is to equalize the amniotic fluid levels between the twins by allowing fluid to pass from the recipient twin's sac to the donor twin's sac. Prior to laser ablation, it was considered that by equalizing the fluid levels, the pressure on the recipient twin is reduced, potentially improving blood flow and reducing the risk of complications associated with TTTS. Septostomy, as a treatment approach, has received relatively less attention or consideration in the management of TTTS and carries a potential risk of cord entanglement.
 

Fetoscopic laser photocoagulation of placental anastomosis
Fetoscopic laser photocoagulation of placental anastomoses is considered the treatment of choice for TTTS stage 2-4 between 16 and 26 weeks of gestation. It can also be considered in stage 1 TTTS specifically when presenting with maternal contractions or short cervix or when close monitoring cannot be offered. [11]. It has also been reported to be offered at a very early (prior to 16 weeks) or very late (after 26 weeks) gestational age. The treatment alters the natural history of the disease and have demonstrated significantly better survival rates than other treatment modalities.[12] Fetoscopic laser photocoagulation of placental anastomoses (FLPC) is a specialized procedure used to treat certain complications that can arise in pregnancies with monochorionic twins, most commonly TTTS. During the procedure, a fetoscope, which is a thin, flexible instrument with a camera and light source, is inserted into the uterus through a small incision in the mother's abdomen. The fetoscope allows the surgeon to visualize the placenta and identify the abnormal blood vessel connections. Diode or Yag laser energy is then used to selectively coagulate or seal these vessels, thereby redirecting blood flow and restoring a more balanced circulation between the twins.
The goal of fetoscopic laser photocoagulation is to address the underlying cause of complications such as TTTS, sFGR or TAPS and improve the outcomes for both twins. By interrupting the abnormal blood flow, this procedure aims to mitigate the risks associated with imbalanced circulation, such as fluid imbalance, growth abnormalities, organ damage, and intrauterine fetal demise.
Fetoscopic laser photocoagulation requires a skilled and experienced surgical team operating in a specialized setting equipped with the necessary instruments and imaging technologies. The procedure is typically performed under local anesthesia for the mother, and careful monitoring of the twins' well-being is maintained throughout.
Following the intervention, close monitoring of the pregnancy continues aiming to diagnose potential complications associated with the procedure, such as development of TAPS or  inadvertent septostomy, etc. [14] Additional interventions or treatments may be required based on the individual circumstances of each case. The success of fetoscopic laser photocoagulation depends on various factors, including the stage of pregnancy, the placental location, experience of the operator, the severity of the complications, and the overall health of the twins. [15]
It's important to note that fetoscopic laser photocoagulation is not suitable for all cases of monochorionic twin pregnancies.  The decision to pursue this intervention is made on an individual basis, considering the risks, potential benefits, and the expertise of the medical team.

Termination of pregnancy
The intricacies associated with monochorionic twin pregnancies, particularly when affected by TTTS, along with the high risk of preterm delivery and adverse outcomes, can lead to some patients considering termination of the pregnancy as a treatment option. However, it is important to note that the availability and feasibility of this option may be subject to local legislation and regulations.

1.    Denbow ML, Cox P, Myles Taylor M, Hammal DM, Fisk NM. Placental angioarchitecture in monochorionic twin pregnancies: relationship to fetal growth, fetofetal transfusion syndrome, and pregnancy outcome. Am J Obstet Gynecol 2000;182:417e26.
2.    Lewi L, Gucciardo L, Van Mieghem T, et al. Monochorionic diamniotic twin pregnancies: natural history and risk stratification. Fetal Diagn Ther 2010;27. 
3.    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):550e5
4.    Diehl W, Diemert A, Grasso D, Sehner S, Wegscheider K, Hecher K. Fetoscopic laser coagulation in 1020 pregnancies with twin-twin transfusion syndrome demonstrates improvement in double-twin survival rate. Ultrasound Obstet. Gynecol. 2017;50(6):728-735. doi:10.1002/uog.17520.
5.    Khalil A, Rodgers M, Baschat A, Bhide A, Gratacos E, Hecher K, Kilby MD, Lewi L, Nicolaides KH, Oepkes D, Raine-Fenning N, Reed K, Salomon LJ, Sotiriadis A, Thilaganathan B, Ville Y. ISUOG Practice Guidelines: role of ultrasound in twin pregnancy. Ultrasound Obstet Gynecol. 2016 Feb;47(2):247-63. doi: 10.1002/uog.15821. Erratum in: Ultrasound Obstet Gynecol. 2018 Jul;52(1):140. PMID: 26577371
6.    Stirnemann JJ, Nasr B, Quarello E, Ortqvist L, Nassar M, Bernard JP, Ville Y. A definition of selectivity in laser coagulation of chorionic plate anastomoses in twin-to-twin transfusion syndrome and its relationship to perinatal outcome. Am J Obstet Gynecol. 2008 Jan;198(1):62.e1-6. doi: 10.1016/j.ajog.2007.06.009. PMID: 18166308., 
7.    Taylor MJ et al., Obstet Gynecol 2002.   Rychik J, Tian Z, Bebbington M, Xu F, McCann M, Mann S, Wilson RD, Johnson MP. 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 Oct;197(4):392.e1-8. doi: 10.1016/j.ajog.2007.06.055. PMID: 17904973.
8.    Espinoza J, Furtun BY, Kailin JA, Altman CA, Seaman RD, Belfort MA, Shamshirsaz AA, Nassr AA, Sanz Cortes M, Donepudi RV, Espinoza AF, Corroenne R, Lee W. Umbilical Artery Doppler Patterns and Right Ventricular Outflow Abnormalities in Twin-Twin Transfusion Syndrome. J Ultrasound Med. 2021 Jan;40(1):71-78. doi: 10.1002/jum.15377. Epub 2020 Jul 10. PMID: 32648616.
9.    Michelfelder E, Gottliebson W, Border W, Kinsel M, Polzin W, Livingston J, Khoury P, Crombleholme T. Early manifestations and spectrum of recipient twin cardiomyopathy in twin-twin transfusion syndrome: relation to Quintero stage. Ultrasound Obstet Gynecol. 2007 Dec;30(7):965-71. doi: 10.1002/uog.5211. PMID: 18044826.
10.    Stirnemann JJ, Mougeot M, Proulx F, Nasr B, Essaoui M, Fouron JC, Ville Y. Profiling fetal cardiac function in twin-twin transfusion syndrome. Ultrasound Obstet Gynecol. 2010 Jan;35(1):19-27. doi: 10.1002/uog.7488. PMID: 20020467
11.    Stirnemann J, Slaghekke F, Khalek N, Winer N, Johnson A, Lewi L, Massoud M, Bussieres L, Aegerter P, Hecher K, Senat MV, Ville Y. Intrauterine fetoscopic laser surgery versus expectant management in stage 1 twin-to-twin transfusion syndrome: an international randomized trial. Am J Obstet Gynecol. 2021 May;224(5):528.e1-528.e12. doi: 10.1016/j.ajog.2020.11.031. Epub 2020 Nov 26. PMID: 33248135.
12.    Lewi L, Gucciardo L, Van Mieghem T, et al. Monochorionic diamniotic twin pregnancies: natural history and risk stratification. Fetal Diagn Ther 2010;27
13.    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: 136-144.
14.    Krispin E, Mustafa HJ, Sun RC, Donepudi R, Espinoza J, Nassr AA, Belfort MA, Sanz Cortes M, Mostafaei S, Harman C, Turan O, Shamshirsaz AA. Iatrogenic chorioamniotic separation and septostomy following fetoscopic laser photocoagulation for twin-twin transfusion syndrome. Ultrasound Obstet Gynecol. 2022 Apr;59(4):506-512. doi: 10.1002/uog.23723. Epub 2022 Mar 10. PMID: 34182599.
15.    Krispin E, Mustafa HJ, Espinoza J, Nassr AA, Sanz Cortes M, Donepudi R, Harman C, Mostafaei S, Turan O, Belfort MA, Shamshirsaz AA. Prediction of dual survival following fetoscopic laser photocoagulation for twin-twin transfusion syndrome. Ultrasound Obstet Gynecol. 2023 Apr;61(4):511-517. doi: 10.1002/uog.26089. PMID: 36191157.

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