Fetal medicine

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Solomonstudy


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Objective
In twin pregnancies, perinatal morbidity and mortality is 7-fold higher than insingletons. In the total group of twin pregnancies, the risk of adverse outcomeis particularly increased in monochorionic (MC) twins, which is explained bythe complications caused by the placental vascular anastomoses. One of the maincauses of mortality and morbidity in MC twins is the twin-to-twin transfusionsyndrome (TTTS), with an incidence of approximately 10%. Expectant managementin this syndrome leads to a mortality of 73-100%. Survivors have a high risk ofmorbidity, due to prematurity and ischemic cerebral damage. In the last decade,fetoscopic laser surgery became available and was recently proven to be thebest method for treatment of TTTS. The aim of fetoscopic laser treatment is tointerrupt the inter-twin circulation through coagulation of the vascularanastomoses on the placental surface.

However, the laser treatment for TTTS isfar from perfect. Treatment with laser can lead to several complications,including intrauterine fetal demise, premature rupture of the membranes andchorioamnionitis and recurrence of TTTS. Double survival rates after lasertreatment are around 60%, and the treatment results in at least one survivor in85% of cases. In the group of survivors, up to 17% of children showneuro-developmental delay on long-term follow-up.

More research is urgently required to further improve the outcome in TTTS pregnancies. One of the concerns with the current treatment and a possible cause of the imperfect outcome is the existence of residual anastomoses found in placentas of MC twins treated with laser. Detailed postnatal injection studies have shown that despite laser surgery, up to 33% of placentas may have one or more residual anastomoses. Most residual anastomoses are extremely small(diameter < 1 mm) en may thus be missed during fetoscopy. These small residual anastomoses can lead to several hematologic complications, including the twin anemia-polycythemia sequence (TAPS). TAPS can lead to severe fetal and neonatal complications including hydrops and perinatal death. In a large series of TTTS-cases in which both twins were alive 1 week after laser surgery, the prevalence of TAPS was reported to be 13%. In addition, recurrence of TTTS with the polyhydramnios-oligohydramnios sequence occurred in 14% of cases. Recurrence of TTTS was also associated with residual anastomoses. Further research to find a way to reduce the rate of residual anastomoses and associated complications, such as TAPS or recurrence of TTTS, is warranted.A possible solution to the problem would be to adopt an alternative laser surgery technique, in which the entire vascular equator is coagulated (Solomontechnique).


Studydesign
Prospective multicenter randomizedcontrolled trial comparing the two surgical techniques. The five participatingcentres are LUMC, Leiden University Medical Center (The Netherlands),University Hospital Leuven (Belgium), University Hospital of Strasbourg(France), University Hospital of Birmingham (England), University Hospital ofMilan (Italy)

Study population
- Inclusion criteria: All TTTS pregnancies eligible for lasersurgery up to 26 weeks gestation. TTTS is defined according to the eurofoetuscriteria (www.eurofetus.org).
- Exclusion criteria: Triplet pregnancies, language problems for informed consent.


Intervention
The two following techniques will be compared

Solomon technique: after identification and coagulation of eachindividual anastomosis, the complete vascular equator is coagulated from oneplacental margin to the other.

Selective technique: The vascular anastomoses are firstidentified and subsequently coagulated one byone.

 

Outcome measures
The aim of the study is to investigate the benefit of theSolomon laser technique in comparison to the selective laser technique in termsof perinatal outcome. The primary outcome measure is acomposite outcome of TAPS and recurrence of TTTS, perinatal mortality andsevere neonatal morbidity.


Power/data analysis
The primary analysis will be done on an intention-to-treat basis. In addition, we will analyse the data using the type of operation actually performed. Power of this trail is based on a single bilateral test of two portions. Previous data were used to compute the required intra-cluster correlation coefficient of 0,58.According to our own data we expect to show a 15% decrease in primary outcome from 60% to 45%. In a classical test we calculated 173 fetuses per arm. The high estimation of the correlation coefficient shows there is an expected correlation between the fetuses per pregnancy. The following power calculations using the formula of the Variance Inflation Factor VIF. With a=0,05,1-b=0,8, P1=45%,P2=60% 273 fetuses or equivalently 137 pregnancies would be needed in each arm.Given a 90% inclusion rate, we calculated that a total of 304TTTS pregnancies need to be recruited. With the expected numbers of TTTS-patients referred to Barcelona, Leuven, Strasbourgand Leiden,this would mean an inclusion period of approximately 2years.

Time schedule
Inclusion period of approximately 2 years.

Funded
ZonMw92003545

Ethical approval

MEC LUMCP07.261

Trialregister
NTR1245

Projectleaders

F.Slaghekke, LUMC, Leiden University Medical Centre, theNetherlands

L. Lewi, University Hospital Leuven, Belgium

R. Favre, University Hospital ofStrasbourg, France

M. Kilby,University Hospital of Birmingam, England

M. Lanna,Children's Hospital V Buzzi Milan,Italy