Title of the project

Full title of proposal: TWIN TO TWIN TRANSFUSION SYNDROME AND MONOCHORIONIC TWINNING EUROPEAN NETWORK

Short title or acronym: EURO-TWIN-2-TWIN

Background and rationale - Monochorionic twin pregnancies are high risk pregnancies

The risk for fetal or neonatal death and long term sequellae in twin pregnancies is about five times greater than in singletons. The incidence of twin pregnancies is about 1/90 pregnancies, of which half of them are identical or monozygotic. Identical twins have a higher risk for complications than non-identical twins. At closer look, it is rather chorionicity (number of placentas) than zygositiy (the number of ovocytes fertilised) which determines outcome of pregnancy. About two in three identical twin pairs are monochorionic (MC). Neonatal literature lists for MC twins a twice as high mortality compared to DC twins and four times as high compared singletons. However perinatal statistics underestimate the problem as even more pregnancies are lost prior to viability. Though data are extremely scarce, recent estimates show a 6 times higher risk for fetal loss rate prior to 24 weeks, a nearly double rate of preterm delivery and of perinatal mortality and a four times higher risk for low birthweight, with all its consequences.

These data show clearly that, although rather rare (3/1,000), MC twins are high risk pregnancies, prone to significant morbidity and mortality. Since chorionicity can be determined by ultrasound examination, patients can in theory timely be identified. Given that many pregnancies are complicated prior to viability, it seems warranted to start surveillance early in gestation. However, because of the lack of data, there are at present no guidelines on how this should be donerealized, let be what action should be taken based on the observations made.

Objectives and primary approaches as per initial application

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The most important difference between MC and DC twin pregnancies is that there are vascular connections in (nearly) all MC placentas, which therefore is probably related to the difference in outcome. A certain pattern of intertwin anastomoses can lead to an even rarer (0,5/1,000 life births), yet more dreadful complication of MC twin pregnancy. Twin-to-twin transfusion syndrome (TTS) is based on a chronic and net transfusion of blood of one fetus to the other, leading to a number of problems, such as preterm rupture of the membranes, preterm labour and birth and intra-uterine fetal death (IUFD). Untreated it is associated with an overall fetal loss rate of 80 % and an over 30 % chance for neurological lesions and mental handicap, seriously affecting later quality of life. The condition is therefore usually treated. Until 1995, the mainstay of therapy has been to drain excessive amniotic fluid, with survival rates of about 50 %, however still with a chance of 20 % for neurologic morbidity. More recently, a more causative approach was proposed by two of the applicants of this proposal. By means of a percutaneous “fetoscopic” operation, anastomosing vessels are visualized and coagulated with laser. Survival rates are about 60-68 % per fetus and a more than 80 % chance for at least one survivor, with a striking reduction in neurologic morbidity to 5 % at birth. It remains at present uncertain which of the two therapies is best, and if there would be a place for a stratified approach. It is proposedhave set up a clinical trial in this respectd.

The general public and even medical professionals are still very much unaware of TTS, let bethe risks associated to MC pregnancies in general, and the importance of diagnosing MC status early in gestation. We have addressed this problem. It is believed that with appropiate means, the efficacy of an ultrasound follow up programme for MC twins can be demonstrated. Also the lack of insight into the pathophysiology of the condition could be overcome. With sufficient prospectively collected data, it may be possible to predict which MC twins will develop TTS, at what stage or with which degree of severity, and whether it would be beneficial to treat TTS in its early stages. For that purpose a consortium of leading clinical centers throughout Europa that have a proven expertise in the field of MC twins were gathered with patient organisations and the medical industries, to achieve the following goals:

Goals:

These are three-fold:

1) To carry out large enough clinical studies to determine the true outcome of MC twin pregnancy, the risk for TTS, what would be the best therapy for TTS and to model MC twin pregnancy in order to predict outcome, the risk for TTS and to improve outcome following therapy;

2) To correlate the most probable underlying cause for the increased risk of MC twins, i.e. the angioarchitecture, to the outcome, in order to use this information for determining best follow up or therapy;

3) To develop new software to complement existing fetal databases for this pathology and new technology for treating selected cases of TTS;

4) to overcome the unawareness of the medical community and the lack of information for citizens about this condition.

The following specific objectives and correlated deliverables are defined:

INFORMATION

• Increase the awareness of medical professionals towards the relevance of early diagnosing MC status, the early signs of TTS and the potential for therapy of TTS. This will be done by organising free courses in each of the memberstates.

• Patients will be offered information in an understandable format via a website. Topics will be MC twin pregnancy, TTS, access to centers treating complicated MC pregnancies, help for trans-national referral, protocols and/or results of clinical studies, hyperlinks to existing medical literature. Modern means will cut on costs and provide the possibility to update on-line. The same medium will be used to disseminate information to medical professionals.

• The website will, at a secured level, be used as the source of information for partners, and be the central tool for project management.

CLINICAL STUDIES

• First a list parameters to follow up MC twins, in utero and postnatal, with particular attention to measures of the Quality of Life of survivors, will be merged in what is called the clinical record file (CRF), the instrument to be used in the clinical studies. This CRF will be made available as printable forms and in electronic format, that will extract parameters from the fetal database in use at the centers participating to the studies.

• Quality of life of neonates born following MC and TTS pregnancies. A retrospective study will review a cohort of babies born following 300 MC and/or TTS pregnancies at the participant’s centers, information lacking at present. This study will provide necessary insight into what the best follow up parameters would be for further use in the prospective studies described below.

• Determination of the “natural” history of MC twinning. A group of 200 MC early diagnosed twin pairs, and a control group of 100 DC twins will be followed up prospectively till the age of one.

• Comparative studies on the treatment of TTS. Given stringent entry criteria, TTS patients will be recruited all over Europe to participate in clinical studies. Both an observational study as randomised clinical trial are proposed, the latter with an estimated number of 2*172 patients.

• An ad hoc external surveillance committee (with experts and patient organisations) is proposed to watch on ethical and safety aspects of the studies, and review interim analyses.

PATHOPHYSIOLOGY AND IMPROVEMENT OF OUTCOME AND THERAPY.

Since it is believed that most of the risks of MC twin pregnancies are related to the presence and pattern of vascular anastomoses, information on the angio-architecture placenta of these pregnancies is essential.

• For well documented pregnancies out of the several clinical studies, 400 placentas will be freely shipped to a central location where they will undergo a standardized detailed examination, with determination of the detailed angioarchitecture.

• Most probably several parameters will define the outcome of MC twin gestation, some of these may be determined in utero. It is proposed to feed all the data collected in the CRF and placental studies, into an earlier proposed computer model, and hoped that this model will help to identify risk or predictive factors for MC and TTS pregnanies.

TECHNICAL INNOVATIONS.

• Industrial partners and clinicians will design additional instrumental developments to construct new endoscopes, minimize the diameters of scopes and laser fibers used in the therapy for TTS.

• With a second industrial partner needed tools for electronic exchange of information on study patients will be developed. This can later be used to market a purpose designed extra modula for existing fetal databases, that covers all essential parameters and help tools for following up MC twins in clinical practice.