Please note that as per June 1st, 2003 the RCT has been completed.

Management of Twin-Twin Transfusion Syndrome. An Open multicentre randomized trial for the evaluation of serial amniodrainage vs endoscopic placental laser surgery with amniodrainage.

Research Proposal

A. Background information
Monochorionic twin pregnancies presenting between 15-25 weeks of gestation with severe twin-to-twin transfusion syndrome are associated with a high risk of miscarriage, perinatal death and chronic handicap in survivors.^1-5

Two methods of treatment have been reported to be effective but no randomised trial has been performed comparing them.

Serial amniodrainage or amniotic fluid volume reduction is historically the most established method of treatment. The rationale of this technique is mainly to prevent polyhydramnios-related miscarriage or preterm delivery. Additionally this would correct the increasing amniotic fluid volume in one sac that is likely to worsen the haemodynamic imbalance between the monochorionic twins by changing the pressure on the placental surface. Although perinatal survival can be improved by serial amniodrainage in up to 61 +/- 22 % of cases, there is a persistent risk of serious chronic handicap in 19 +/- 5% of the survivors.^{2-4,6,8,12-18,21-24}

A more recent development in the management of this condition is the use of fetoscopy and laser coagulation to interrupt the placental vascular communications between the twins which are a prerequisite for the development of the syndrome.^{9,10,19,25,26} This is always accompanied by one amniodrainage at the end of the surgical treatment. Recent data about this treatment in a multicentre study reported the experience in the management of 132 completed pregnancies with severe twin-to-twin transfusion syndrome.¹⁹ The median gestation at surgery was 21 weeks. The total number of surviving babies was 144 (55%) and there was at least one survivor in 97 (73%) cases. At a minimum age of one year neurological handicap was suspected in six (4.2%) of the survivors.

Because of the rarity of the syndrome, any one centre will see only a handful of cases each year. The study has therefore been designed as an open multicentre trial.

B. Purpose of the Project
To compare the safety and efficacy of two different treatment methods in severe TTS before 26+0 weeks.

Primary aims of the study:

1. To compare survival in TTS treated by either technique.
2. To compare the rate of neurological morbidity associated with the use of either treatment.

Secondary aims of the study:

1. To compare the rate of maternal and obstetrical complications associated with either treatment.
2. To compare the rate of neonatal morbidity other than neurological in each treatment arm.

To compare the safety and efficacy of two different treatment methods in severe TTS before 26+0 weeks.
Primary aim of the study: to compare survival in TTS treated by either treatment.
Secondary aim of the study: to compare morbidity in the survivors and in the patients.

C. Description of the Study

Subjects
Pregnant women followed at any of the participating institutions.

Patients would be eligible for the study if the diagnosis of severe twin-to-twin transfusion syndrome (TTS) before 26+0 weeks is established.

Ineligibility criteria
1. Major fetal anomaly.
2. Ruptured membranes.
3. Maternal condition mandating delivery.
4. Previous amniodrainage or other invasive therapy for the same condition.
5. Multiple pregnancies of higher order than 2.

Exclusion criteria.
1. Lack of confirmation of chorionicity after delivery.
2. Late diagnosis of major fetal anomaly.

The diagnosis of TTS will be established on the following ultrasound criteria:
1. Twin pregnancy known to be monochorionic on a first trimester scan and / or a single placental mass and concordant sex on the second trimester scan.
2. Polyhydramnios in one sac with a deepest vertical pool of amniotic fluid of at least
    8.0 cm at less than 20 weeks’ gestation,
    10.0 cm at more than 20 weeks.
    The polyhydramnios should be related to polyuria with a distended fetal bladder during most of the examination period.
3. Oligohydramnios (stuck twin) in the other sac with a deepest vertical pool of amniotic fluid of at most 2.0 cm. The oligohydramnios should be likely related to fetal oliguria with a collapsed bladder during most of the examination period.

Study groups
Patients will be randomly assigned, by using a computer-generated randomisation list, to one of the following:
Group 1: Amniodrainage
Group 2: Laser coagulation of the communicating placental vessels

Description of treatments under study
Group 1:
Amniodrainage
An amniodrainage will be performed under ultrasound guidance in the polyhydramniotic sac. This can be performed with/without local analgesia, using an 18-gauge needle with a free drainage technique or an aspiration device, but the end-point should be to reduce the deepest pool of fluid down to a deepest pool of maximum of 5-6 cms.
The patient will undergo weekly ultrasound and a repeat amniodrainage will be performed when polyhydramnios has recurred whether this is responsible for maternal discomfort or only fulfils the ultrasound criteria defined with the entry criteria. Other additional therapy and follow up is specified below.

Group 2
Laser coagulation of the communicating placental vessels
An appropriate site of entry on the maternal abdomen will be chosen to avoid injury to the placenta or the fetuses and to allow access through the recipient sac to the intertwin membrane, ideally perpendicular to the long axis of the donor fetus. The procedure can be carried out under local, regional or general anaesthesia.
Under continuous ultrasound visualisation, an endoscope of less than 3 mm in diameter housed in a cannula is introduced transabdominally into the amniotic cavity of the recipient twin. A 400 or 600 m m diameter Nd:YAG laser is then passed down the side-arm of the cannula to 1 cm beyond the tip of the fetoscope. A combination of ultrasonographic and direct vision is used to examine systematically the chorionic plate along the whole length of the intertwin membrane to identify the crossing or anastomosing vessels. Coagulation is performed using an output of 30 to 60 Watts for one to three seconds from a distance of about 1 cm.²⁰

Subsequently, amniotic fluid is drained through the endoscope cannula to obtain a deepest pool of 5-6 cm on ultrasonographic examination. The patients can be managed as outpatients or kept in hospital for observation at the discretion of the treating physician. Other additional therapy and follow up is specified below.

Additional therapy in Group 1 and Group 2
Tocolytic therapy (indomethacin or diclofenac per rectum and/or magnesium sulfate or beta-mimetics intravenously) and antibiotics (a third generation cephalosporin intravenously) can be given prophylactically to cover the operative period for 24-48 hours.

Follow-up and ultrasound measurements
Prior to and following each procedure (at each observation), three groups of ultrasonographic measurements will be recorded for each fetus(see tables):

1. Biometry measurements: biparietal diameter, head circumference, abdominal circumference, femur length.
2. Functional ultrasound measurements: ascites, pleural effusion, pericardial effusion, skin edema, and deepest vertical pocket of amniotic fluid in each sac
3. Doppler measurements: Fetal umbilical artery, middle cerebral artery, inferior vena cava and/ or ductus venosus pulsatility indices.

After delivery, the placenta will be checked for chorionicity.

1. Perinatal survival and survival at 7-12 months of age (global).
1. Perinatal survival of at least one fetus.
2. Neurological morbidity at 7-12 months.

1. Maternal complications
2. Premature Rupture of Membranes
3. Preterm labor requiring tocolysis.
4. Neonatal neurological morbidity.
5. Other neonatal morbidity

Survival estimates
will be defined according to the following
Perinatal period. Is defined from the moment of treatment to 28 days after birth.
Global survival. Refers to the percentage of fetuses alive, over the total number of fetuses.
Survival of at least one fetus. Percentage of pregnancies with at least one survivor over the total number of pregnancies.

Neurological morbidity at 7-12 months
The presence of significant neurological morbidity will be defined on the basis of:
-abnormal motor development (including cerebral palsy): according to Bayley’s scales of infant development.²⁷
-abnormal mental development: according to Bayley’s scales. ²⁷

Neonatal morbidity
It is defined as the presence of any of the following:
-intraventricular haemorrhage: diagnosed and graded according to papile’s system of grading of severity ²⁸:

• Grade I: isolated germinal matrix hemorrhage
• Grade II: IVH with normal ventricular size
• Grade III: IVH with ventricular dilatation
• Grade IV: IVH with parenchimal hemorrhage.

-leukomalacia: diagnosed and scored according to de Vries et al: ²⁹

• Grade I: transient periventricular (PV) densities for more than 7 days.
• Grade II: transient PV densities evolving into small localized frontoparietal cysts.
• Grade III: PV densities evolving into extensive PV cystic lesions.
• Grade IV: densities extending into the deep white matter evolving into cystic lesions.

-convulsions
-hypoxic-ischemic encephalopathy: defined as a disturbance in cerebral function manifested in the first few day by altered level of conciousness, a disturbance in muscle tone and posture, and seizures, associated with signs of peripartum hypoxia.³⁰

Maternal complications
Any of the following will be considered as maternal complications:
-maternal death
-intraperitoneal bleeding, in 2 categories: (1) requiring blood transfusion and (2) requiring laparotomy
-ascites, defined as the presence of a measurable pocket of fluid in the superior hemiabdomen as assessed by ultrasound.
-chorioamnionitis, as defined by fever (=>38ºC), abnormal leukocyte count with bands, uterine tenderness and/or contractions.
-any other complication that could be related to the surgical procedure

Premature Rupture of Membranes
It is defined on rupture of membranes before the onset of labor. It will be categorized in (1) preterm (occurring before the 37^th week of pregnancy) and (2) term.

Preterm labor requiring tocolysis
Onset of uterine regular contractions requiring the use of any tocolytic medication before the 37^th week of pregnancy.

Sample size and subjects
A total of 172 patients will be included in each arm of the study in order to demonstrate a difference in survival as well as a difference of 5-15% in handicap in the survivors. (a=0.05, ß = 0.20) Interim analyses will be performed after 72 and 144 patients will have been included respectively.

D. Potential side effects associated with treatments under study
The perinatal mortality of severe twin-to-twin transfusion syndrome without intervention is between 60% and 95%.
Amniodrainage, especially if repeated in the same pregnancy, carries the risk of preterm labour and delivery, and preterm premature rupture of the membranes with resulting preterm delivery.
The same risks can be attributed to fetoscopic placental surgery and this occurred in less than 10% of the cases in the pilot study of 132 cases.

General considerations
The present study has no ethical implications, as no additional procedures with respect to those currently available in patient-care protocols are to be performed.
Should a patient elect not to participate in the research protocol, the standard treatment performed in her institution will still be recorded with the same parameters not in this study, but in an observational register. Each patient is allowed to opt out of the study, without having to give any reasons for that.
The study conforms to the Helsinki Declaration on clinical studies on human subjects. Adherence to all existing ethical and safety provisions applicable in the countries in which the research is carried out is warranted by the requirement of approval of the protocol by local ethics committees at each participating institution.

Consent procedure
Written consent will be obtained by the investigator or his designee prior to enrolment in the study. This should be done accordingly to the requirement of each individual local Ethics committee. However an example is given in Annex 1.

Confidentiality
The confidentiality of the data will be maintained within legal limits. Any published data will not contain the names or other identifying patient information.

Known benefits of the therapies and risk/benefit ratio
As previously mentioned, untreated severe TTS carries a 60-95% mortality rate and a perinatal morbidity of around 30%. Perinatal survival with amniodrainages and laser surgery has been reported to be 60+/- 22% and 55% respectively. Severe perinatal morbidity was 19 +/-5% and 4.2% respectively.
Because the fetal loss rate for untreated TTS is so high, , and there is up to 10% procedure-related risk of pregnancy loss, the risk-benefit ratio is in favour of treatment. Both treatments involved in the study are associated to an improved outcome. Any decrease in mortality/morbidity for these fetuses/neonates is of great benefit to the patient as well as to the society. Establishing which of these two treatments is the most effective will be of great benefit to future patients with this syndrome.

F. Practical considerations
Randomization
Computer randomization via the Internet, or via a 24 hour telephone.

Costs
There will be no extra costs to the patient participating in the study

Experience of participating centres in the treatments under study
All calculations have been made on the understanding that the centres involved in laser surgery will have performed at least 10 cases or would perform them with the help of an operator experienced in this domain. The experience required for amniodrainages would also be 10 procedures. It is assumed that this corresponds to the learning curve to allow for an acceptable experience prior to enter the trial.

G. Data analysis
Proposed main analysis:
-evaluation of comparability of study groups
-evaluation of potential differences in the main outcome measurements, and secondary measurements between study groups

Proposed secondary analysis:
-evaluation of potential differences for each category of secondary outcome measurements
-evaluation of prognostic factors, either related to ultrasound or to therapy features, (hypothesis to be defined)

Interim evaluation and analysis of results
Foreseen after completion of 75 % of the study, to be monitored by an external consultant.
Whenever in a treatment arm 3 serious maternal complications or mortalities would occurr, the Eurofoetus group will meet to discuss the conditions, and judge if it is warranted to continue the study.

1. Weir PE, Ratten GJ, Beischer NA. Acute polyhydramnios - a complication of monozygous twin pregnancy. Br J Obstet Gynaecol 1979;86:849-53.
2. Larroche JC, Droulle P, Delezoide AL, Narcy F, Nessmann C. Brain damage in monozygous twins. Biol Neonate 1990;57:261-78.
3. Gonsoulin W, Moise KJ Jr, Kirshon B, Cotton DB, Wheeler JM, Carpenter RJ Jr. Outcome of twin-twin transfusion diagnosed before 28 weeks of gestation. Obstet Gynecol 1990;75:214-6.
4. Saunders NJ, Snijders RJM, Nicolaides KH. Therapeutic amniocentesis in twin-twin transfusion syndrome appearing in the second trimester of pregnancy. Am J Obstet Gynecol 1992;166:820-4.
5. Machin GA, Still K. The twin-twin transfusion syndrome: vascular anatomy of monochorionic placentas and their clinical outcomes, in Keith LG, Papiernik E, Keith DM, Luke B (eds): Multiple pregnancy: epidemiology, gestation and perinatal outcome. New York, The Parthenon Publishing Group, 1995, pp 367-94.
6. Pinette MG, Pan Y, Pinette SG, Stubblefield PG. Treatment of twin-twin transfusion syndrome. Obstet Gynecol 1993;82:841-6.
7. Bajoria R, Wigglesworth J, Fisk NM. Angioarchitecture of monochorionic placentas in relation to the twin-twin transfusion syndrome. Am J Obstet Gynecol 1995;172:856-63.
8. Trespidi L, Boschetto C, Caravelli E, Villa L, Kustermann A, Nicolini U. Serial amniocentesis in the management of twin-twin transfusion syndrome: When is it valuable? Fetal Diagn Ther 1997;12:15-20.
9. 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;75:1046-53.
10. Ville Y, Hecher K, Ogg D, Warren R, Nicolaides K. Successful outcome after Nd:YAG laser separation of chorioangiopagus-twins under sonoendoscopic control. Ultrasound Obstet Gynecol 1992;2:429-31.
11. Ville Y, Hyett J, Hecher K, Nicolaides K. Preliminary experience with endoscopic laser surgery for severe twin-twin transfusion syndrome. N Engl J Med 1995;332: 224-7.
12. Mahony BS, Petty CN, Nyberg DA, Luthy DA, Hickok DE, Hirsch JH.. The stuck twin phenomenon: ultrasonographic findings, pregnancy outcome and management with serial amniocentesis. Am J Obstet Gynecol 1990;163:1513-22.
13. Urig MA, Clewell WH, Elliott JP. Twin-twin transfusion syndrome. Am J Obstet Gynecol 1990;163:1522-6.
14. Elliott JP, Urig MA, Clewell WH. Aggressive therapeutic amniocentesis for treatment of twin-twin transfusion syndrome. Obstet Gynecol 1991;77:537-40.
15. Reisner DP, Mahony BS, Petty CN et al. Stuck twin syndrome: outcome in thirty-seven consecutive cases. Am J Obstet Gynecol 1993;169:991-5.
16. Bruner JP, Rosemond RL. Twin-to-twin transfusion syndrome. A subset of the twin oligohydramnios-polyhydramnios sequence. Am J Obstet Gynecol 1993;169:925-30.
17. Dickinson JE. Severe twin-twin transfusion syndrome: current management concepts. Aust NZ J Obstet Gynecol 1995;35:16-21.
18. Dennis LG, Winkler CL. Twin-to-twin transfusion syndrome: Aggressive therapeutic amniocentesis. Am J Obstet Gynecol 1997;177:342-9.
19. Ville Y, Hecher K, Sebire N, Gagnon A, Nicolaides K. Endoscopic laser coagulation in the management of severe twin to twin transfusion syndrome. Br J Obstet Gynecol. 1998; in press.
20. Van Peborgh P, Rambaud C, Ville Y. Effect of laser coagulation on placental vessels: histological aspects. Fetal Diagn Ther 1997;12:32-35.
21. Bernirschke K, Kim CK. Multiple pregnancy. N Engl J Med 1973;288:1276-84.
22. Fusi L, Gordon H. Twin pregnancy complicated by single intrauterine death. Problems and outcome with conservative management. Br J Obstet Gynaecol 1990;97:511-6.
23. Liu S, Bernirschke K, Scioscia AL, Mannino FL. Intrauterine death in multiple gestation. Acta Genet Med Gemellol 1992;41:5-26.
24. Bejar R, Vigliocco G, Gramajo H et al. Antenatal origin of neurologic damage in newborn infants II. Multiple gestations. Am J Obstet Gynecol 1990;162:1230-6.
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27. Bayley’s scales of infant development. The psychological corporation press, New York, 1959.
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30. Prenatal and Neonatal Medicine 1996; 1: 160.

This has been elaborated with the help of and reviewed by Twin2Twin, the UK Twin to Twin Transfusion Syndrome Association.

Study Title: Management of Twin-Twin Transfusion Syndrome. A Multicentre Randomised Trial for the evaluation of Serial Amniodrainage vs Endoscopic laser placental surgery with amniodrainage.

Name of Patient:

The current condition I have and its implications
I understand that I am expecting identical twins and that my pregnancy is complicated by a condition known as twin-twin transfusion syndrome.
This means mainly that the twins share the same placenta and that connected blood vessels within my placenta are causing an imbalanced flow of blood from one twin to another.

This makes one twin produce large amounts of urine and is responsible for the large size of my uterus. This also causes some cardiac overload in this twin making it at risk of developing heart failure.

The other twin is often but not always much smaller than the other twin and is unable at the moment to produce normal amounts of urine urine. This baby is at risk of chronic malnutrition and lack of oxygen and could die because of this.

I understand that when the condition is as severe as it is in my case, the survival chances for my twins are less than 10% if no treatment is received.

Alternatively I can benefit from one of the two most established method of treatment of these condition, being serial amniodrainage and placental surgery with amniodrainage.

Other therapies have been described, but not documented enough at this stage.

I have read and I understand the documentation provided to me by my doctors about these two treatment methods and the purpose of this study.

I understand that by electing to participate in this study, I have an equal chance of receiving either treatment chosen for me at random by a computer (like a flip of the coin). If I decide not choose to participate in the study, my doctors will proceed with the best treatment available in their hands and my preference, even if it is not known whichever therapy is the best.

If I have been assigned to the amniodrainage group, after some anaesthetic is given to the skin and deeper in the uterus, a needle will be placed through my belly into the larger twin’s sac. A tube will then be attached to the needle and fluid will be drained until a normal amount of fluid remains. This will take approximately 30 minutes. I will undergo additional removal of fluid later in my pregnancy if too much fluid reaccumulates in the same twin’s sac.

If I have been assigned to the placental surgery group, after a local / regional / general anaesthesia is given, a bigger needle will be introduced through my belly into the bigger twin’s sac. A small telescope and a laser will then be passed through the needle and some vessels on the placenta will be destroyed to attempt to prevent the abnormal flow of blood from one twin to another. The excessive amount of amniotic fluid will be removed through the same needle. This will take approximately 30 minutes.

As part of either treatment group, I will be asked to return weekly for an ultrasound scan to determine the health of my twins, the amount of fluid in each sac, and the way the blood is moving in the babies. After birth my babies will be followed up to the age 12 months or longer.

I give permission to record into an electronic file all medical information on myself, the procedure and my babies, in an anonymous way that is connected to the condition. Anonymity is guaranteed.

I can always discontinue my participation to this study.

Signature of patient Date

Person obtaining the consent Date

Witness’s signature Date

This consent form is not valid without the Local Ethical Committee approval.