Management of Twin-Twin Transfusion Syndrome

Christian Bamberg and Kurt Hecher

Introduction

Twin-twin transfusion syndrome (TTTS) is a serious complication of monochorionic (MC) multiple gestations. Monochorionicity is the fundamental underlying prerequisite for TTTS because the fetuses share a single placenta, and almost all cases exhibit placental vascular communications between the umbilical circulations.

The process of placental angiogenesis in MC placentas remains elusive. In the first trimester, multiple anastomoses are present in a random and balanced pattern. It has been hypothesised that in cases of TTTS, during the second trimester, vascular connections are progressively and asymmetrically reduced, leading to dominance of arterio-venous vessels from donor to recipient, allowing a shift of blood.³ Twin-twin transfusion syndrome results from the imbalanced chronic blood flow through placental anastomoses. The donor com­monly exhibits hypovolemia, oliguria and oligohydramnios, while the recipient exhibits hypervolemia, polyuria and polyhydramnios as an expression of fluid overload. These obser­vations emphasise the unique role of the angio-architecture of MC placentation in TTTS development, and may explain why TTTS complicates only 10-15% of MC twin pregnancies during mid-gestation.

Twin-Twin Transfusion Syndrome Diagnosis

Twin-twin transfusion syndrome is diagnosed by ultrasound, and all MC pregnancies should be screened biweekly by sonography starting at a gestational age of 16 weeks until 26 weeks for this specific complication.⁵ Delayed TTTS detection results in deterioration of prognosis in terms of worse perinatal outcome. The main sonographic finding in cases of TTTS is a huge discrepancy in the amount of fluid between the twins' amniotic sacs. The donor twin presents with a small or invisible urinary bladder and oligo- or anhydramnios (deepest vertical pocket of < 2 cm), and often becomes stuck to the uterine wall or placenta. The recipient twin displays an oversized urinary bladder and polyuric polyhydramnios, defined by a deepest vertical pocket of > 8 cm before 20 weeks and > 10 cm after 20 weeks. These amniotic fluid cut-off values are recom­mended by the Eurofoetus group, but in the United States, most fetal medicine specialists use a cut-off of 8 cm regardless of gestational age. Several pitfalls are faced in amniotic fluid evaluation. Sometimes the donor twin may be wrapped within its membranes and floating freely in an amniotic sling in the polyhydramnios of the recipient twin (cocoon sign). Additionally, the single largest vertical pocket must be measured free from fetal parts or umbilical cord and is dependent on uterine tension. The probe should be gently positioned on the maternal abdomen, perpendicular to the longitudinal axis of the uterus and without tilting.

Monochorionic-monoamniotic (MCMA) twin pregnancies rarely develop TTTS (2-6% prevalence) because there are usually plenty of anastomoses between the umbilical cord insertions, which are often placentally inserted close to each other. In cases of MCMA TTTS, the common amniotic sac exhibits polyhydramnios.

To encourage early detection, healthcare providers should inform mothers about the clinical symptoms of TTTS, which include sudden maternal abdominal swelling dispropor­tionate to gestational age, abdominal discomfort, back pain, a tense and oversized uterus and early contractions. If a woman reports these signs, an ultrasound should be performed immediately and she should be referred to a fetal surgery unit if TTTS is diagnosed.

Twin-Twin Transfusion Syndrome Prediction in the First Trimester

All women carrying a multiple pregnancy should be offered a prenatal ultrasound examination at 11-13 gestational weeks to assess viability, chorionicity, crown-rump length, ductus venosus Doppler velocity waveforms and nuchal translucency. First-trimester identification of MC twins with a high risk for the development of TTTS enables improved surveillance. A recent small prospective study demonstrated that the best predictive marker for TTTS was nuchal translucency discordance of ≥ 20% (AUC, 0.79; 95% CI, 0.59-0.99).⁶ However, the positive predictive value was only 36%, meaning ultrasound screening is still mandatory. In a large retrospective study including 1,274 MC diamniotic twin pregnancies, the authors analysed data from routine ultrasound examinations at 11 -13 gestational weeks.⁷ The rate of fetal loss or need for endoscopic laser surgery at < 20 gestational weeks was 24.1% in the subgroup of fetuses with NT ≥ 95th percentile and 40.5% in those with NT ≥ 99th percentile. Moreover, a systematic review and meta-analysis found that TTTS development was significantly predicted by discrep­ancy in NT and crown-rump length of > 10%, NT > 95th percentile or abnormal ductus venosus flow on first-trimester ultrasound examination.⁸ We performed a prospective study, using three-dimensional ultrasound with colour Doppler imaging to investigate the umbilical coiling index in untreated TTTS cases⁹.

Twin-Twin Transfusion Syndrome Staging

Prenatal ultrasound staging systems have been developed to provide a standardised method of describing TTTS severity and predicting perinatal outcome. These categorical staging systems were designed to describe a heterogeneous and dynamic clinical entity. The Quintero classification was introduced more than 20 years ago and remains the most frequently used system owing to its simplicity.¹⁰

At all Quintero stages, polyhydramnios is present in the recipient twin and oligo/ anhydramnios is present in the donor twin. The donor twin's bladder is visible during stage I and cannot been seen at stage II. Stage III is characterised by critically abnormal Doppler findings, including absent or reversed end-diastolic flow in the umbilical artery, and/or absent or reversed flow during a-wave in the ductus venosus. Stage IV includes

Table 13.1 TheQui ntero Staging Classification

Data are shown as n (%).

hydrops. Table 13.1 summarises the Quintero staging criteria and the prevalence of each stage in our own TTTS laser surgery population.¹¹

The Quintero system has several important limitations. For instance, a donor twin may have a visible bladder but abnormal Doppler findings. Two research groups from the United States have incorporated additional cardiovascular parameters for neonatal outcome pre­diction, based on findings that recipient twins may show signs of heart failure even at early TTTS stages.^12,13 In contrast, donor twins generally show normal echocardiograms. Importantly, the stage may remain stable, regress or rapidly progress, and TTTS often does not progress in a predictable or chronological manner. Intrauterine fetal death can occur at stage I without deterioration to more advanced stages.

Twin-Twin Transfusion Syndrome Treatment

Cases of mild-to-moderate TTTS show amniotic fluid discordance but do not fulfil the criteria of severe TTTS. Membrane folding is frequently observed, but the donor twin is not stuck to the uterine wall. In such cases, weekly ultrasound follow-up is required until the presence or absence of severe TTTS is clear. Most moderate cases remain stable and do not necessitate intervention.

Fetoscopic Laser Surgery

Without treatment, severe TTTS carries an 80-90% risk of perinatal mortality due to intrauterine fetal death, miscarriage or extremely preterm delivery.¹⁴ For severe TTTS, fetoscopic laser surgery is the first-line therapy because it is the only causal therapy by a single intervention. On the other hand, serial amnioreduction of the recipient's polyhydramnios is a symptomatic treatment that reduces the intrauterine pressure and may prolong the pregnancy. However, amniodrainage does not solve the causative problem of the disease. Notably, amnioreduction should be avoided prior to fetoscopy as it may reduce the feasibility and success of laser surgery due to bleeding, chorioamniotic separation or membrane rupture.

Evidence clearly indicates that fetoscopic laser coagulation of placental vascular anasto­moses is superior to serial amniodrainages in severe TTTS cases. Senat and co-workers conducted a multicentre randomised controlled trial (RCT) comparing fetoscopic laser therapy with serial amnioreductions in cases of TTTS at between 15 and 26 gestational weeks.¹⁵ The trial was stopped early because interim analysis revealed that compared to serial amnioreductions (n = 70), fetoscopic laser therapy (n = 72) resulted in higher survival of at least one twin, higher gestational age at delivery and better neurological outcomes at all stages.

Technique

Fetoscopy should only performed by highly experienced fetal medicine experts. In prepar­ation for the intervention, careful ultrasound scanning provides the surgeon with essential information such as the extent of the placenta with both cord insertions, localisation of the stuck twin and the expected vascular equator on the placental surface. Twin-twin transfu­sion syndrome is not associated with an increased risk of chromosomal abnormalities, but fetuses with MC placentation exhibit an increased incidence of congenital abnormalities. Therefore, a detailed fetal anomaly scan including fetal echocardiogram and brain evalu­ation should always be performed before laser intervention.

Before surgery, a single shot of prophylactic antibiotics is administered and magne­sium is administered intravenously to inhibit contractions. After 24 gestational weeks, we administer tractocile as a tocolytic agent, combined with a course of antenatal steroids. Following local anaesthesia of the skin and myometrium, an operating sheath with obturator is inserted percutaneously into the recipient’s sac under ultrasound guidance. An optimal insertion site is essential for visualising the entire vascular equator, and should be selected opposite the assumed vascular anastomoses. In cases with an anterior placenta, the entry site should be chosen lateral to the placental margin. Special endoscopes have been developed with a 30° optical system and inte­grated steering levers for bending of the laser fibre tip upwards to the placenta, as well as curved operating sheaths After insertion of the scope through the sheath, the fetal surgeon will identify several important landmarks such as the cord insertion site of the recipient twin and the inter-twin membrane on the chorionic plate. This is followed by placental mapping, in which the different types of anastomoses are characterised. Diode or Nd:YAG lasers have optimal energy absorbance in the spectrum of haemoglobin and are commonly used to coagulate the anastomoses selectively.

During fetoscopy, the surgeon should also visualise the limbs of the recipient twin because this fetus will sometimes also have polycythaemia and may show signs of throm­bosis, primarily in the lower extremities. The laser procedure is completed by draining excess amniotic fluid through the cannula to achieve a deepest vertical pocket of 5-6 cm. The patient is usually discharged between 24 and 48 hours after the procedure and then undergoes weekly ultrasound follow-up examinations. These should always include Doppler blood flow studies of the umbilical artery, middle cerebral artery peak systolic velocity and ductus venosus.

Complications of Fetoscopic Twin-Twin Transfusion Syndrome Treatment

Maternal Complications

Fetoscopy is considered safe for the mother when performed by an experienced specialist. Sacco et al. recently summarised the outcomes of 9,403 fetoscopic surgery patients and reported a severe maternal complication rate of ~2% and a minor complication rate of ~4%.¹6 However, due to the lack of standardised evaluation of maternal complications, the incidence of complications may by underreported.

Fetal Complications

Laser surgery may lead to single (21.7%) or double (3.0%) intrauterine fetal demise.¹¹ In up to 60% of cases, TTTS is accompanied by selective intrauterine growth restric­tion due to unequal placental sharing.¹⁷ The main risk factors for intrauterine donor death are growth discordance > 30%, reverse end-diastolic flow in the umbilical artery after laser surgery and a marginal or velamentous cord insertion.¹⁸ Risk factors for death of the recipient twin include a reversed a-wave in the ductus venosus and hydrops.¹⁹

The most common complication of fetoscopic laser surgery is iatrogenic preterm premature rupture of the membranes (PPROM), which mainly occurs due to a persistent membrane defect at the trocar insertion site. Many experts in this field share the opinion that the amniotic access is the Achilles' heel of operative fetoscopy. Stirnemann and colleagues reported the follow-up of 1,017 cases after TTTS treatment with percutaneous fetoscopic laser.²⁰ Gestational age at surgery before 17 weeks was a significant risk factor for PPROM. However, reducing the diameter of the inserted instruments has decreased the PPROM risk. Observational management is recom­mended, but preterm delivery occurs on average two weeks earlier than in cases without PPROM. Membrane separation may occur at the entry site of the trocar, and this is associated with increased risk of PPROM and consecutively with a higher risk of preterm delivery before 32 weeks. As mentioned earlier, prematurity is a major challenge in TTTS and the most important risk factor for neonatal mortality and morbidity.

After fetoscopic laser surgery in TTTS, residual placental anastomoses may lead to post-laser twin anaemia-polycythemia sequence (TAPS) and recurrent TTTS. Twin anaemia-polycythemia sequence is defined as a chronic feto-fetal net transfusion of erythrocytes owing to a few missed minuscule arterio-venous anastomoses, which may occur in 3-16% of cases depending on the laser technique.^21,22 It is characterised by large inter-twin haemoglobin differences without discrepancy in amniotic fluid vol­ume. Prenatal diagnosis is made by Doppler ultrasound revealing a significant dis­cordance of peak systolic velocities in the middle cerebral arteries of both twins. There is recurrence of TTTS with a prevalence of 5%, which is characterised by either ongoing or inversed discrepancies in amniotic fluid volumes and bladder fillings, owing to missed larger arterio-venous anastomoses.

Outcomes after Laser Treatment for Twin-Twin Transfusion Syndrome

Perinatal Survival

A recent systematic review summarised 25 years of fetoscopic laser coagulation for TTTS.²³ The authors reported the outcomes of 3,868 women from 34 studies and highlighted the large variations in caseloads and outcomes among different fetal medicine centres. Over the review time period, the mean survival of both twins significantly increased from 35% to 65% and the mean survival of at least one twin significantly increased from 70% to 88%. The average gestational age at birth was 32.4 ± 1.3 weeks.

In 2017, we published a single-centre study of laser therapy in 1,020 pregnancies with severe TTTS.¹¹ The rate of survival of both twins significantly increased from 50% in the first group of 200 cases to 69.5% in the last group of 220 cases (p = 0.018) and reached a plateau after 600 procedures. The rate of at least one survivor showed a non-significant trend of increase from 80.5% to 91.8% (p = 0.072). The mean gestational age at delivery with at least one live-born twin was 33.7 ± 3.2 weeks. The introduction of 30° scopes with a special mechanism to deflect the laser fibre for anterior placentas led to an improvement of the double survival rate, which was no longer different from posterior placentas.

Neurodevelopment and the Cardiovascular System

We recently published a detailed review of long-term outcomes for MC twins after laser therapy for TTTS, which includes neurodevelopmental and cardiovascular outcomes, growth, renal function and ischemic events.²⁴ Approximately 2% of survivors after feto- scopic laser surgery exhibit fetal brain lesions (equally distributed between donors and recipients), which may be ischemic or haemorrhagic.²⁵ Significant risk factors include recurrent TTTS and post-laser TAPS following incomplete laser surgery. Importantly, follow-up studies of TTTS cases treated with laser surgery have reported varying rates of cerebral palsy and neurodevelopment impairment, possibly due to differences in method­ology, heterogeneity within small case series and lack of uniform criteria regarding out­come. A review of 13 studies reported a 6.1% prevalence of cerebral palsy and a 9.8% prevalence of neurodevelopmental impairment.²⁶ Preterm delivery was an independent risk factor for neurodevelopmental impairment after laser treatment. Other important risk factors included increased gestational age at intervention, higher Quintero stage, perinatal severe cerebral injury and low birthweight. In a recent investigation of 434 children who underwent laser surgery for TTTS, follow-up at two years of age revealed a 3% incidence of severe neurodevelopment impairment and a 2% incidence of cerebral palsy.²⁷ Increased survival rates after TTTS laser surgery have not been associated with a rising risk of neurological damage, suggesting that an improvement of the technique with growing experience is shown at some specialised high volume centres.

Congenital heart defects are more frequent among twins with TTTS compared to uncomplicated MC twins and singletons. Cohort studies have examined the prevalence of heart disease in children after laser therapy for TTTS. Herberg and co-workers analysed 62 survivors at the age of 10 years and found that 6 (9.7%) exhibited structural heart defects.²⁸ The main finding was pulmonary stenosis, which may affect both former recipient and donor twins.

Management of Stage I Twin-Twin Transfusion Syndrome

Stage I TTTS is defined as discordance of amniotic fluid between the two fetuses, combined with a still visible bladder in the donor twin and normal fetal Doppler blood flow findings in both twins. We currently lack important data regarding the natural history of stage I TTTS cases. Between 10% and 50% of cases (pooled average, 27%) show disease progression to more advanced stages but, unfortunately, there are no clear indicators for predicting progression.²⁹

Management of stage I TTTS remains controversial. A systematic review and meta­analysis suggested that the pooled overall survival was 79% with expectant treatment, 77% with amnioreduction, 68% with laser treatment performed after progression and 84% with laser surgery as the first-line choice.²⁹ In the absence of maternal complications, conserva­tive management with weekly surveillance may be offered at stage I.

A multicentre RCT has been conducted to compare conservative management to immediate laser surgery in stage I TTTS cases between 16+0 and 26+6 gestational weeks. The women were randomly assigned to undergo primary laser surgery within 72 hours or conservative management with weekly ultrasound follow-up. Within the conservative management group, laser treatment was performed in cases that exhibited progression to stage II or higher, severe maternal discomfort due to polyhydramnios and/or cervical shortening < 15 mm. Recently, this study was prematurely completed after 117 inclusions. Intact survival at 6 months was seen in 84 of 109 (77%) expectant cases and in 89 of 114 (78%) immediate surgery cases (p=0.88). In patients followed expectantly, 41% remained stable with a dual intact survival of 86%, whereas it was 78% and 71% followed immediate or rescue surgery, respectively., although these differences were not statistically significant. The authors could not identify any meaningful predictors of progression. (Stirnemann J et al., Am J Obstet Gynecol 2021).

From a practical point of view and based on our experience, visualisation of the donor twin's bladder filling at stage I is often dependent on the duration of the examination. Slight bladder filling without dynamic changes indicates absent voiding due to impaired urine production. Therefore, in our unit, we usually offer laser treatment in all cases with stage I TTTS, particularly in the presence of maternal symptoms and a short cervix.³⁰

Premature Cervical Shortening

Cervical shortening in TTTS may presumably be caused by excessive uterine distension due to polyhydramnios. However, the definition of a short cervix is inconsistent (< 10, 20 or 25 mm), and the optimal management (vaginal progesterone, cervical pessary or cerclage) is unclear due to the lack of randomised trials. A multicentre retrospective cohort study (n = 163) evaluated the benefit of cervical cerclage in cases with a cervical length of < 25 mm at the time of fetoscopic laser coagulation. Approximately half of the women received a cerclage, but cerclage placement did not significantly prolong pregnancy (28.8 weeks vs 29.1 weeks at delivery with and without cerclage, respectively) or improve survival rates.³¹ Two smaller single-centre studies investigated cerclage performance after laser surgery in TTTS patients with an extremely short cervix (< 10 mm or < 15 mm).^32,33 Both research groups demonstrated that emergency cerclage placement was feasible and improved peri­natal outcome. Overall, the benefit of cerclage for TTTS patients with a short cervix remains controversial. Notably, it is clear that premature cervical shortening should not be an exclusion criteria for laser treatment.

Optimal Laser Technique

Although it is a consensus that all vascular anastomoses should be ablated during the fetoscopic laser procedure, it is questionable whether all connecting vessels can be identified and coagulated. Patent anastomoses have been detected in up to one-third of placentas after treatment using standard fetoscopic laser technique.³⁴ This prompted the development of a modified laser method called the Solomon technique. After identification and selective sequential coagulation of the anastomoses, the laser is used to draw a thin line from one placental edge to the other, connecting the laser dots. The rationale underlying this method is that coagulating the entire vascular equator (dichorionisation) minimises the risk of residual anastomoses that are not visible to the eye.

In the RCT Solomon trial, 274 women were randomly assigned to treatment with the Solomon technique (n = 139) or the standard selective laser method (n = 135).³⁴ The Solomon technique was associated with significant reductions of recurrent TTTS (1% vs 7%) and post-laser TAPS (3% vs 16%), and the treatment groups did not differ in perinatal mortality or severe neonatal morbidity. The procedure time was identical in both groups; however, the total amount of laser energy was approximately twofold higher with the Solomon technique (9,275 Joule vs 4,933 Joule; p < 0.0001).

Concerns have been raised about whether it is justified to laser healthy placental tissue between the anastomoses, resulting in a greater extent of placental injury.³⁶ Additionally, a recent report described an increased risk of placental abruption after Solomon laser treatment.³⁷ The authors concluded that the greater risk of placental abruption with the Solomon technique might be due to more extensive tissue damage of the thinner areas at the placenta edges. The results of these studies must be interpreted cautiously and further long­term investigations are required to determine the correct use of the Solomon technique. In our clinical experience, we favour a partial Solomon technique in which we coagulate an area of neighbouring anastomoses by drawing a line along the vascular equator without unnecessarily sacrificing placental tissue where no vessels at all are detectable on the chorionic plate.

Twin-Twin Transfusion Syndrome in Triplets, before Gestational Week 17 and after Gestational Week 26

Monochorionic triplets may also develop TTTS and such cases should be treated with laser intervention. Among triplet pregnancies, 75% are dichorionic-triamniotic. In MC triplets, the number of donors and recipients varies depending on the placental architecture. If there are two recipients, both amniotic cavities have to be entered to gain access to all anasto­moses. D'Antonio and co-workers summarised the perinatal outcomes of triplets after laser treatment for TTTS. Their analysis included eight studies and a total of 126 triplet pregnan­cies (104 dichorionic triamniotic and 22 monochorionic-triamniotic).³8 Perinatal survival rates of at least one triplet, at least two triplets and all three triplets were 94.1%, 80.2% and 51%, respectively. In general, these pregnancies carried higher risks for extremely preterm birth and for fetal and perinatal loss than twins.

Some evidence suggests that laser treatment for TTTS at a gestational age of < 17 weeks or > 26 weeks is feasible and safe and may improve perinatal outcome.³⁹ However, only 2.5% of all TTTS patients are affected before 17 gestational weeks. In such cases, the perinatal outcome after conventional laser therapy is comparable to that between 17 and 26 weeks; there is an increased risk of PPROM within one week after laser treatment and a hypothetical chance of spontaneous regression. The prevalence of TTTS after a gestational age of 26 weeks is 4-8%. In such cases, laser therapy may lead to delayed delivery, recovery of both twins in utero and improved neonatal outcome. The presence of turbid amniotic fluid and the increased difficulty of coagulating larger placental vessels may occur at higher gestational weeks.

Timing and Mode of Delivery after Laser Treatment

From our perspective, in the absence of post-laser complications, delivery can be scheduled at between 36/0 and 37/0 gestational weeks. Some experts suggest delivery at 34 gestational weeks, but evidence is lacking for such management. In terms of delivery mode, we offer a vaginal delivery for cases meeting the following criteria: > 32 gestational weeks, vertex presentation of the first twin, appropriate fetal weight and absence of severe weight discord­ance, normal Doppler and fetal heart tracing results, presence of a trained maternal fetal medicine specialist who is familiar with internal manoeuvres and signed informed consent.

Conclusion

In conclusion, TTTS occurs due to chronic unbalanced blood shunting between MC multiples across placental vascular connections. The treatment of choice is fetoscopic laser coagulation of the anastomoses. For stage I TTTS, some fetal medical centres offer conservative manage­ment with close surveillance, but laser treatment is recommended for cases involving a short cervix, maternal discomfort and increasing polyhydramnios. Perinatal survival has signifi­cantly improved over the past 30 years since the introduction of fetoscopic laser surgery for TTTS. High-volume centres achieve 70% double twin survival and > 90% survival of at least one twin. Laser therapy should be offered in specialised fetal medicine centres that perform at least 20 procedures per surgeon annually. We have demonstrated that centralisation of TTTS laser treatment improves the survival rates for both twins and the individual learning curve. The ultimate goal of TTTS laser surgery should be double survival with normal long-term neurodevelopment by avoidance of very preterm delivery. There remains a need for prospect­ive studies with standardised evaluation of long-term outcomes.

Key Points

• Severe TTTS affects 10-15% of MC multiples and usually occurs between 16 and 26 gestational weeks.

• All MC pregnancies should be screened and monitored by ultrasound every two weeks until delivery.

• Large discordance of amniotic fluid volume is the main ultrasound finding in TTTS.

• Evidence suggests that fetoscopic laser coagulation of placental anastomoses is the gold standard for TTTS treatment, which is the most frequently performed intrauterine surgery nowadays.

• Specialised laser centres achieve double and at least one survival rates of 70% and > 90%, respectively.

• Centralisation of specialised care for TTTS results in reduced complications and increased intact double survival.

• Long-term studies show incidences of severe neurodevelopmental impairment of 3-13%, which is independently associated with low gestational age at delivery.

References

1. Benirschke K, Masliah E. The placenta in multiple pregnancy: outstanding issues. Reprod Fertil Dev 2001;13:615-22.

2. Zhao DP, de Villiers SF, Slaghekke F et al. Prevalence, size, number and localization of vascular anastomoses in monochorionic placentas. Placenta 2013;34:589-93.

3. Sebire NJ, Talbert D, Fisk NM. Twin-to- twin transfusion syndrome results from dynamic asymmetrical reduction in placental anastomoses: a hypothesis. Placenta 2001;22:383-91.

4. Bamberg C, Hecher K. Twin-to-twin transfusion syndrome: Controversies in the diagnosis and management. Best Pract Res Clin Obstet Gynaecol 2022; doi: 10.1016/j. bpobgyn.2022.03.013. Online ahead of print.

5. Khalil A, Rodgers M, Baschat A et al. ISUOG practice guidelines: role of ultrasound in twin pregnancy. Ultrasound Obstet Gynecol 2016;47:247-63.

6. Mogra R, Saaid R, Tooher J, Pedersen L, Kesby G, Hyett J. Prospective validation of first-trimester ultrasound characteristics as predictive tools for twin-twin transfusion syndrome and selective intrauterine growth restriction in monochorionic diamniotic twin pregnancies. Fetal Diagn Ther 2020;47(4):321-7.

7. Cimpoca B, Syngelaki A, Litwinska E, Muzaferovic A, Nicolaides KH. Increased nuchal translucency at 11-13 weeks' gestation and outcome in twin pregnancy. Ultrasound Obstet Gynecol 2020;55:318-25.

8. Stagnati V, Zanardini C, Fichera A et al. Early prediction of twin-to-twin transfusion syndrome: systematic review and meta-analysis. Ultrasound Obstet Gynecol 2017;49:573-82.

9. Bamberg C, Diemert A, Glosemeyer P, Tavares de Sousa M, Hecher K. Discordance of umbilical coiling index between recipients and donors in twin­twin transfusion syndrome. Placenta 2019;76:19-22.

10. Quintero RA, Morales WJ, Allen MH, Bornick PW, Johnson PK, Kruger M.

Staging of twin-twin transfusion syndrome. J Perinatol 1999;19:550-5.

11. 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;50:728-35.

12. Michelfelder E, Gottliebson W, Border W et al. Early manifestations and spectrum of recipient twin cardiomyopathy in twin­twin transfusion syndrome: relation to Quintero stage. Ultrasound Obstet Gynecol 2007;30:965-71.

13. 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-e8.

14. Berghella V, Kaufmann M. Natural history of twin-twin transfusion syndrome.

J Reprod Med 2001;46:480-4.

15. 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;351:136-44.

16. Sacco A, Van der Veeken L, Bagshaw E et al. Maternal complications following open and fetoscopic fetal surgery:

a systematic review and meta-analysis. Prenat Diagn 2019;39:251-68.

17. Groene SG, Tollenaar LSA, Van

Klink JMM et al. Twin-twin transfusion syndrome with and without selective fetal growth restriction prior to fetoscopic laser surgery: short- and long-term outcome. J Clin Med 2019 Jul 3;8(7):969.

18. Snowise S, Moise KJ, Johnson A, Bebbington MW, Papanna R. Donor death after selective fetoscopic laser surgery for twin-twin transfusion syndrome. Obstet Gynecol 2015;126:74-80.

19. Skupski DW, Luks FI, Walker M et al. Preoperative predictors of death in twin-to-twin transfusion syndrome treated with laser ablation of placental anastomoses. Am J Obstet Gynecol 2010;203(388):e1-e11.

20. Stirnemann J, Djaafri F, Kim A et al. Preterm premature rupture of membranes is a collateral effect of improvement in perinatal outcomes following fetoscopic coagulation of chorionic vessels for twin­twin transfusion syndrome: a retrospective observational study of 1092 cases. BJOG 2018;125:1154-62.

21. Habli M, Bombrys A, Lewis D et al. Incidence of complications in twin-twin transfusion syndrome after selective fetoscopic laser photocoagulation: a single­center experience. Am J Obstet Gynecol 2009;201(417):e1-e7.

22. Robyr R, Lewi L, Salomon LJ et al. Prevalence and management of late fetal complications following successful selective laser coagulation of chorionic plate anastomoses in twin-to-twin transfusion syndrome. Am J Obstet Gynecol 2006;194:796-803.

23. Akkermans J, Peeters SH, Klumper FJ, Lopriore E, Middeldorp JM, Oepkes D. Twenty-five years of fetoscopic laser coagulation in twin-twin transfusion syndrome: a systematic review. Fetal Diagn Ther 2015;38:241-53.

24. Hecher K, Gardiner HM, Diemert A, Bartmann P. Long-term outcomes for monochorionic twins after laser therapy in twin-to-twin transfusion syndrome. Lancet Child Adolesc Health 2018;2:525-35.

25. Stirnemann J, Chalouhi G, Essaoui M et al. Fetal brain imaging following laser surgery in twin-to-twin surgery. BJOG 2018;125:1186-91.

26. Van Klink JM, Koopman HM, Rijken M, Middeldorp JM, Oepkes D, Lopriore E. Long-term neurodevelopmental outcome in survivors of twin-to-twin transfusion syndrome. Twin Res Hum Genet 2016;19:255-61.

27. Spruijt MS, Lopriore E, Tan R et al. Long­term neurodevelopmental outcome in twin-to-twin transfusion syndrome: is there still room for improvement? J Clin Med 2019 Aug 15;8(8):1226. https://doi.org /10.3390/jcm8081226

28. Herberg U, Bolay J, Graeve P, Hecher K, Bartmann P, Breuer J. Intertwin cardiac status at 10-year follow-up after intrauterine laser coagulation therapy of severe twin-twin transfusion syndrome: comparison of donor, recipient and normal values. Arch Dis Child Fetal Neonatal Ed 2014;99:F380-F385.

29. Khalil A, Cooper E, Townsend R, Thilaganathan B. Evolution of stage 1 twin-to-twin transfusion syndrome (TTTS): systematic review and meta-analysis. Twin Res Hum Genet 2016;19:207-16.

30. Bamberg et al. Neither the differentiation between twin-twin transfusion syndrome Stages I and II nor III and IV makes a difference regarding the probability of double survival after laser therapy. Ultrasound Obstet Gynecol 2020.

31. Papanna R, Habli M, Baschat AA et al. Cerclage for cervical shortening at fetoscopic laser photocoagulation in twin­twin transfusion syndrome. Am J Obstet Gynecol 2012;206(425):e1-e7.

32. 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;28:1256-61.

33. Aboudiab MS, Chon AH, Korst LM, Llanes A, Ouzounian JG, Chmait RH. Management of twin-twin transfusion syndrome with an extremely short cervix. J Obstet Gynaecol 2018;38:359-62.

34. Lopriore E, Middeldorp JM, Oepkes D, Klumper FJ, Walther FJ, Vandenbussche FP. Residual anastomoses after fetoscopic laser surgery in twin-to- twin transfusion syndrome: frequency, associated risks and outcome. Placenta 2007;28:204-8.

35. Slaghekke F, Lopriore E, Lewi L et al. Fetoscopic laser coagulation of the vascular equator versus selective coagulation for twin-to-twin transfusion syndrome: an open-label randomised controlled trial. Lancet 2014;383:2144-51.

36. Quintero RA, Kontopoulos E, Chmait RH. Laser treatment of twin-to-twin transfusion syndrome. Twin Res Hum Genet 2016;19:197-206.

37. Lanna MM, Faiola S, Consonni D, Rustico MA. Increased risk of placental abruption after Solomon laser treatment of twin-twin transfusion syndrome. Placenta 2017;53:54-6.

38. D’Antonio F, Thilaganathan B, Toms J et al. Perinatal outcome after fetoscopic laser surgery for twin-to-twin transfusion syndrome

in triplet pregnancies. BJOG 2016;123:328-36.

39. 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(197):e1-e7.