What did the TRUFFLE 1 study show?

The optimal timing of delivery of growth-restricted fetuses has, until the TRUFFLE study, been dependent on the experience of the individual clinician and/or institution. The clinician must consider and balance the risks of stillbirth, obstetric intervention, prematurity, neonatal death and long-term neurodevelopmental disorders. Our group sought to determine whether an optimal monitoring modality and threshold for delivery could be determined by randomising to in 1:1:1 ratio to 1. Fetal cardiotocography short-term variability (CTG STV)  2. Fetal ductus venosus pulsatility index (DV p95), or 3. Late fetal ductus venosus a-wave changes (DV no A) in pregnancies between 26 and 32 weeks gestation with very preterm growth restriction.

Fetal outcome was better than expected from contemporary reports: perinatal death was uncommon (8%) and 70% survived without severe neonatal morbidity. The intervals to delivery, death and severe morbidity were related to the presence and severity of maternal hypertensive conditions.The proportion of infants surviving without neuroimpairment did not differ between the CTG STV,  DV p95 and DV no A groups. Of survivors, more infants where women were randomly assigned to delivery according to late ductus changes were free of neuroimpairment when compared with those randomly assigned to CTG, but this was accompanied by a non-significant increase in perinatal and infant mortality.

These findings have led to significant discussion at national and international level and are being incorporated into the next versions of national guidance documents.

Who was involved in the TRUFFLE 1 study?

C Lees (London/Cambridge), N Marlow (London), A van Wassenaer-Leemhuis (Amsterdam), B Arabin (Zwolle/Marburg), CM Bilardo (Amsterdam/Groningen), C Brezinka (Innsbruck), S Calvert (London), JB Derks (Utrecht), A Diemert (Hamburg), JJ Duvekot (Rotterdam), E Ferrazzi (Milan), T Frusca  (Brescia/Parma), W Ganzevoort (Amsterdam), K Hecher (Hamburg), P Martinelli (Naples), E Ostermayer (Munich), AT Papageorghiou (London), D Schlembach (Graz/Jena), KTM Schneider (Munich), B Thilaganathan (London), T Todros (Turin),  A Valcamonico (Brescia), GHA Visser (Utrecht), H Wolf (Amsterdam)

The TRUFFLE 2 Study

The TRUFFLE group now aims to address the question of the optimal monitoring and thresholds for delivery in late-onset fetal growth restriction, from 32-36 weeks gestation. To date no intervention other than delivery has been reported to have an impact on late onset fetal growth restriction. However, increasing the prevalence of even late-preterm birth by intervening in pregnancies thought to be at risk is associated with increased morbidity for the woman (from Caesarean section, induction of labour) and her baby (increased risk of poor condition at birth and the consequences of neonatal admissions), through to even small but significant increases in the risk of special needs at school.

A preliminary feasibility study (TRUFFLE 2 Feasibility Study: audit of current practice) is needed to identify suitable neonatal outcomes for a trial on which a trial size calculation can be based. These outcomes would be evaluated in a randomised management trial (TRUFFLE 2 RCT).  Hence the aim of this study is to perform a prospective observational audit of practice and feasibility study (TRUFFLE 2 Feasibility Study) to identify predictors of perinatal outcome in a comprehensive third trimester ultrasound monitoring strategy that will inform the design of a formal trial (TRUFFLE 2 RCT). This feasibility study is the largest of its type, started in 2017 and is likely to complete in early/mid 2018.

The TRUFFLE 2 group remains a cohesive partnership of leading UK, European and Scandinavian perinatal centres where there are excellent fetal medicine, obstetric and neonatal services. This group now numbers over 30. Its members are committed to undertaking prospective research in high risk perinatology and fetal growth restriction.

Published research papers

turned_in How to monitor pregnancies complicated by fetal growth restriction and delivery before 32 weeks: post-hoc analysis of TRUFFLE study.
Ganzevoort W, Mensing Van Charante N, Thilaganathan B, Prefumo F, Arabin B, Bilardo CM, Brezinka C, Derks JB, Diemert A, Duvekot JJ, Ferrazzi E, Frusca T, Hecher K, Marlow N, Martinelli P, Ostermayer E, Papageorghiou AT, Schlembach D, Schneider KTM, Todros T, Valcamonico A, Visser GHA, Van Wassenaer-Leemhuis A, Lees CC, Wolf H; TRUFFLE Group.

turned_in The association of neonatal morbidity with long-term neurological outcome in infants who were growth restricted and preterm at birth: secondary analyses from TRUFFLE.
Van Wassenaer-Leemhuis AG, Marlow N, Lees C, Wolf H; TRUFFLE investigators.

turned_in Is middle cerebral artery Doppler related to neonatal and 2-year infant outcome in early fetal growth restriction?
Stampalija T, Arabin B, Wolf H, Bilardo CM, Lees C; TRUFFLE investigators.

turned_in The TRUFFLE study; fetal monitoring indications for delivery in 310 IUGR infants with 2 year's outcome delivered before 32 weeks of gestation.
Visser GH, Bilardo CM, Derks JB, Ferrazzi E, Fratelli N, Frusca T, Ganzevoort W, Lees C, Napolitano R, Todros T, Wolf H, Hecher K; TRUFFLE group investigators.

turned_in Phase-rectified signal averaging method to predict perinatal outcome in infants with very preterm fetal growth restriction- a secondary analysis of TRUFFLE-trial.
Lobmaier SM, Mensing van Charante N, Ferrazzi E, Giussani DA, Shaw CJ, Müller A, Ortiz JU, Ostermayer E, Haller B, Prefumo F, Frusca T, Hecher K, Arabin B, Thilaganathan B, Papageorghiou AT, Bhide A, Martinelli P, Duvekot JJ, van Eyck J, Visser GH, Schmidt G, Ganzevoort W, Lees CC, Schneider KT; TRUFFLE investigators.

turned_in Longitudinal study of computerized cardiotocography in early fetal growth restriction.
Wolf H, Arabin B, Lees CC, Oepkes D, Prefumo F, Thilaganathan B, Todros T, Visser GHA, Bilardo CM, Derks JB, Diemert A, Duvekot JJ, Ferrazzi E, Frusca T, Hecher K, Marlow N, Martinelli P, Ostermayer E, Papageorghiou AT, Scheepers HCJ, Schlembach D, Schneider KTM, Valcamonico A, van Wassenaer-Leemhuis A, Ganzevoort W; TRUFFLE group.

turned_in Delivery of the growth-restricted preterm fetus - Author's reply.
Lees CC; TRUFFLE group.

turned_in 2 year neurodevelopmental and intermediate perinatal outcomes in infants with very preterm fetal growth restriction (TRUFFLE): a randomised trial.
Lees CC, Marlow N, van Wassenaer-Leemhuis A, Arabin B, Bilardo CM, Brezinka C, Calvert S, Derks JB, Diemert A, Duvekot JJ, Ferrazzi E, Frusca T, Ganzevoort W, Hecher K, Martinelli P, Ostermayer E, Papageorghiou AT, Schlembach D, Schneider KT, Thilaganathan B, Todros T, Valcamonico A, Visser GH, Wolf H; TRUFFLE study group.

turned_in Reply: To PMID 24078432.
Lees C; TRUFFLE group.

turned_in Perinatal morbidity and mortality in early-onset fetal growth restriction: cohort outcomes of the trial of randomized umbilical and fetal flow in Europe (TRUFFLE).
Lees C, Marlow N, Arabin B, Bilardo CM, Brezinka C, Derks JB, Duvekot J, Frusca T, Diemert A, Ferrazzi E, Ganzevoort W, Hecher K, Martinelli P, Ostermayer E, Papageorghiou AT, Schlembach D, Schneider KT, Thilaganathan B, Todros T, van Wassenaer-Leemhuis A, Valcamonico A, Visser GH, Wolf H; TRUFFLE Group.

turned_in The TRUFFLE study--a collaborative publicly funded project from concept to reality: how to negotiate an ethical, administrative and funding obstacle course in the European Union.
Lees C, Baumgartner H.