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Randomized trial of timing of delivery in early preterm fetal growth restriction based on early and late fetal Doppler venous changes versus cardiotocography. Acronym TRUFFLE = Trial of Umbilical and Fetal Flow in Europe.

Projectomschrijving

De enige behandeling van vroeg preterme foetale groeibeperking bestaat uit foetale monitoring en tijdige geboorte, waarbij gebalanceerd wordt tussen te vroeg ingrijpen, met meer kans op complicaties van vroeggeboorte, of te laat ingrijpen met meer kans op orgaanschade door zuurstof of voedingstekort. De TRUFFLE studie onderzocht of toevoeging van ductus venosus (DV) Doppler doorstromingsmeting (pulsatility index, PI) aan de standaard foetale bewaking met cardiotocografie (CTG) verbetering zou kunnen geven van overleving zonder neurologische beperking op langere termijn.
De conclusie van het onderzoek is dat gecombineerde foetale bewaking in gespecialiseerde perinatale centra met DV en CTG van zwangere vrouwen met ernstige preterme foetale groeibeperking de kans op gezond overleven van de kinderen kan vergroten.

Producten

Titel: Is middle cerebral artery Doppler related to neonatal and 2-year infant outcome in early fetal growth restriction?
Auteur: Stampalija, Tamara, Arabin, Birgit, Wolf, Hans, Bilardo, Caterina M., Lees, Christoph, Brezinka, C., Derks, J.B., Diemert, A., Duvekot, J.J., Ferrazzi, E., Frusca, T., Ganzevoort, W., Hecher, K., Kingdom, J., Marlow, N., Marsal, K., Martinelli, P., Ostermayer, E., Papageorghiou, A.T., Schlembach, D., Schneider, K.T.M., Thilaganathan, B., Thornton, J., Todros, T., Valcamonico, A., Valensise, H., van Wassenaer-Leemhuis, A, Visser, G.H.A., Aktas, A., Borgione, S., Chaoui, R., Cornette, J.M.J., Dieh
Magazine: American Journal of Obstetrics and Gynecology
Titel: Comparative analysis of 2-year outcomes in GRIT and TRUFFLE trials
Auteur: Ganzevoort, W. Thornton, J. G. Marlow, N. Thilaganathan, B. Arabin, B. Prefumo, F. Lees, C. Wolf, H. Grit Study Group Truffle Study Group
Magazine: Ultrasound Obstet Gynecol
Link: https://www.ncbi.nlm.nih.gov/pubmed/31125465
Titel: Fetal monitoring indications for delivery and 2-year outcome in 310 infants with fetal growth restriction delivered before 32 weeks' gestation in the TRUFFLE study
Auteur: Visser, G. H. A., Bilardo, C. M., Derks, J. B., Ferrazzi, E., Fratelli, N., Frusca, T., Ganzevoort, W., Lees, C. C., Napolitano, R., Todros, T., Wolf, H., Hecher, K.
Magazine: Ultrasound Obstet Gynecol
Titel: The association of neonatal morbidity with long-term neurological outcome in infants who were growth restricted and preterm at birth: secondary analyses from TRUFFLE (Trial of Randomized Umbilical and Fetal Flow in Europe)
Auteur: Van Wassenaer-Leemhuis, AG, Marlow, N, Lees, C, Wolf, H
Magazine: BJOG-International Journal of Obstetrics and Gynaecology
Titel: Longitudinal study of computerized cardiotocography in early fetal growth restriction
Auteur: Wolf, H., Arabin, B., Lees, C. C., Oepkes, D., Prefumo, F., Thilaganathan, B., Todros, T., Visser, G.?H.?A., Bilardo, C.?M., Derks, J.?B., Diemert, A., Duvekot, J.?J., Ferrazzi, E., Frusca, T., Hecher, K., Marlow, N., Martinelli, P., Ostermayer, E., Papageorghiou, A. T., Scheepers, H. C. J., Schlembach, D., Schneider, K. T. M., Valcamonico, A., van Wassenaer-Leemhuis, A., Ganzevoort, W.
Magazine: Ultrasound Obstet Gynecol
Titel: 2 year neurodevelopmental and intermediate perinatal outcomes in infants with very preterm fetal growth restriction (TRUFFLE): a randomised trial
Auteur: Lees, Christoph C, Marlow, Neil, van Wassenaer-Leemhuis, Aleid, Arabin, Birgit, Bilardo, Caterina M, Brezinka, Christoph, Calvert, Sandra, Derks, Jan B, Diemert, Anke, Duvekot, Johannes J, Ferrazzi, Enrico, Frusca, Tiziana, Ganzevoort, Wessel, Hecher, Kurt, Martinelli, Pasquale, Ostermayer, Eva, Papageorghiou, Aris T, Schlembach, Dietmar, Schneider, K T M, Thilaganathan, Baskaran, Todros, Tullia, Valcamonico, Adriana, Visser, Gerard H A, Wolf, Hans
Magazine: Lancet
Titel: How to monitor pregnancies complicated by fetal growth restriction and delivery before 32 weeks: post-hoc analysis of TRUFFLE study
Auteur: Ganzevoort, W., Mensing Van Charante, N., Thilaganathan, B., Prefumo, F., Arabin, B., Bilardo, C. M., Brezinka, C., Derks, J. B., Diemert, A., Duvekot, J. J., Ferrazzi, E., Frusca, T., Hecher, K., Marlow, N., Martinelli, P., Ostermayer, E., Papageorghiou, A. T., Schlembach, D., Schneider, K. T. M., Todros, T., Valcamonico, A., Visser, G. H. A., Van Wassenaer-Leemhuis, A., Lees, C. C., Wolf, H.
Magazine: Ultrasound Obstet Gynecol
Titel: Severe fetal growth restriction at 26-32 weeks: key messages from the TRUFFLE study
Auteur: Bilardo, C. M., Hecher, K., Visser, G. H. A., Papageorghiou, A. T., Marlow, N., Thilaganathan, B., Van Wassenaer-Leemhuis, A., Todros, T., Marsal, K., Frusca, T., Arabin, B., Brezinka, C., Derks, J. B., Diemert, A., Duvekot, J. J., Ferrazzi, E., Ganzevoort, W., Martinelli, P., Ostermayer, E., Schlembach, D., Valensise, H., Thornton, J., Wolf, H., Lees, C.
Magazine: Ultrasound Obstet Gynecol
Link: https://www.ncbi.nlm.nih.gov/pubmed/28938063?dopt=Citation
Titel: Perinatal morbidity and mortality in early-onset fetal growth restriction: cohort outcomes of the trial of randomized umbilical and fetal flow in Europe (TRUFFLE)
Auteur: Lees, C., Marlow, N., Arabin, B., Bilardo, C. M., Brezinka, C., Derks, J. B., Duvekot, J., Frusca, T., Diemert, A., Ferrazzi, E., Ganzevoort, W., Hecher, K., Martinelli, P., Ostermayer, E., Papageorghiou, A. T., Schlembach, D., Schneider, K. T. M., Thilaganathan, B., Todros, T., van Wassenaer-Leemhuis, A., Valcamonico, A., Visser, G. H. A., Wolf, H.
Magazine: Ultrasound Obstet Gynecol
Titel: Effects of Antenatal Betamethasone on Fetal Doppler Indices and Short Term Fetal Heart Rate Variation in Early Growth Restricted Fetuses
Auteur: ratelli, N. Prefumo, F. Wolf, H. Hecher, K. Visser, G. H. A. Giussani, D. Derks, J. B. Shaw, C. J. Frusca, T. Ghi, T. Ferrazzi, E. Lees, C. C. Truffle Group Truffle Group authors Truffle Group collaborating authors
Magazine: European Journal of Obstetrics & Gynecology and Reproductive Biology
Link: https://www.ncbi.nlm.nih.gov/pubmed/31476786
Titel: Phase-rectified signal averaging method to predict perinatal outcome in infants with very preterm fetal growth restriction- a secondary analysis of TRUFFLE-trial
Auteur: Lobmaier, Silvia M., Mensing van Charante, Nico, Ferrazzi, Enrico, Giussani, Dino A., Shaw, Caroline J., Müller, Alexander, Ortiz, Javier U., Ostermayer, Eva, Haller, Bernhard, Prefumo, Federico, Frusca, Tiziana, Hecher, Kurt, Arabin, Birgit, Thilaganathan, Baskaran, Papageorghiou, Aris T., Bhide, Amarnath, Martinelli, Pasquale, Duvekot, Johannes J., van Eyck, Jim, Visser, Gerard H.A., Schmidt, Georg, Ganzevoort, Wessel, Lees, Christoph C., Schneider, Karl T.M., Bilardo, Caterina M., Brezinka,
Magazine: American Journal of Obstetrics and Gynecology
Titel: year neurodevelopmental and intermediate perinatal outcomes in infants with very preterm fetal growth restriction (TRUFFLE): a randomised trial
Auteur: Christoph C Lees, Neil Marlow, Aleid van Wassenaer-Leemhuis, Birgit Arabin, Caterina M Bilardo, Christoph Brezinka, Sandra Calvert, Jan B Derks, Anke Diemert, Johannes J Duvekot, Enrico Ferrazzi, Tiziana Frusca, Wessel Ganzevoort, Kurt Hecher, Pasquale Martinelli, Eva Ostermayer, Aris T Papageorghiou, Dietmar Schlembach, K T M Schneider, Baskaran Thilaganathan, Tullia Todros, Adriana Valcamonico, Gerard H A Visser, Hans Wolf, for the TRUFFLE study group
Magazine: Lancet

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Eindverslag

Tot eind september werden 375 vrouwen geregistreerd en 332 vrouwen gerandomiseerd. 175 vrouwen werden in Nederlandse centra geincludeerd.
Inclusie is gering vertraagd doordat een van de Nederlandse centra (Zwolle) wegens vertrek van de hoofdonderzoeker, tijdelijk niet includeerde. Per 1-10 zal inclusie dar weer hervat worden. Voorts is het Academisch Ziekenhuis Groningen, na een wat lange voorbereiding, nu in staat om te participeren. We gaan er van uit dat de voortgang van de studie het komende jaar weer het eerdere tempo zal oppakken.
De gemiddelde zwangerschapsduur bij randomisatie is 29 weken (SD 1.5). Verlenging van de zwangerschap na inclusie is gemiddeld 1.5 weken. Gemiddeld geboortegewicht is 965 gram (SD 274). Dit betekent dat voldoende vrouwen bij een zeer vroege zwangerschapsduur zijn geïncludeerd. Dit is van belang aangezien, als een verschil in uitkomst tussen de randomisatie groepen optreedt, dit naar verwachting het meest uitgesproken zal zijn bij de meest premature kinderen.
Follow up met Bayley III werd vorig jaar georganiseerd en kinderartsen of psychologen van alle centra zijn inmiddels getraind om de Bayley III uit te voeren. Kinderen geboren tijdens het eerste studie jaar werden inmiddels getest met slechts zeer geringe uitval.

Samenvatting van de aanvraag

Optimal management of severe early fetal growth restriction is one of the greatest challenges in Obstetrics. In case of abnormal fetal monitoring obstetricians are often uncertain when to deliver these babies and how to balance between the complications of extreme preterm delivery and the risks of prolonged intrauterine exposure to malnutrition, hypoxia and antepartum death. Prospective observational research by the study group and others has provided evidence that Doppler measurement of the fetal ductus venosus (DV) may be the best parameter to guide timing of delivery in these pregnancies. However this hypothesis needs further evidence. The objective of this multi-centre randomised protocol, approved by the editorial board of the Lancet, is to determine which technique results in optimal timing of delivery of early preterm growth restricted infants: DV measurement (two different cut-offs - 1. mild or 2.severe abnormality) and 3. traditional monitoring based on cardiotocography with measurement of short term variation (STV) will be compared. Criteria for inclusion aim at selecting a group of early and severe growth restricted fetuses with a gestational age between 26 and 32 weeks. Randomisation will assign fetuses to the three branches. The primary outcome is normal neurological outcome at 2 years, corrected for gestational age at delivery, without minor or major sequelae, examined by Griffith`s Mental Developmental Scale. Two years is the earliest age to evaluate infant development. Composite adverse infant outcome, defined by major neonatal morbidity and mortality until discharge, is an intermediate endpoint, which will be used for safety monitoring and for an interim report. The hypothesis of the study is that among preterm growth-restricted infants timing delivery when the fetal DV is just marginally or severely abnormal, i.e. before the onset of severe fetal hypoxemia, increases the rate of normal infant neurological outcome compared with timing of delivery based on severe changes in fetal heart STV (control group). 570 women should be randomised to detect a difference of 50% normal neurological outcome in the control group to 66.6% in any of the DV groups (OR 2.0) with alpha 0.05 and beta 0.8, allowing for 20% mortality. Based on estimates by the participating centres (236 inclusions/year), the study group expects to complete the randomisation within three years. Twenty European perinatal centres are participating. Five are Dutch centres and so 1/4 of all patients will be recruited in the Netherlands. All participants have extensive experience in fetal Doppler and monitoring and all are convinced that a randomised trial should be performed before wide scale application of DV Doppler measurement can be advised for fetal monitoring. This study will enable development of guidelines concerning timing of delivery in early preterm fetal growth restriction, which is of importance for all obstetric high care centres, which treat this condition, both in the Netherlands and abroad. Implementation of results of the trial will be facilitated by the fact that the study is performed in a large number of university clinics all over Europe and that treatment of early preterm fetal growth restriction is generally limited to such clinics. Centres from each European country have applied locally for funding and medical ethical approval. Most participants will start inclusion during the first half of 2005. We request financial support to perform this important study in the Netherlands and for data management of the complete study to ascertain quality of data acquisition. Duration of the complete study will be 5 years (3 years randomisation and 2 years follow-up). Three years after start of the study the intermediate endpoint can be reported. Results of the study will be published anonymously on behalf of the study group.

Onderwerpen

Kenmerken

Projectnummer:
94506556
Looptijd: 100%
Looptijd: 100 %
2005
2009
Onderdeel van programma:
Gerelateerde subsidieronde:
Projectleider en penvoerder:
Dr. H. Wolf
Verantwoordelijke organisatie:
Amsterdam UMC - locatie AMC