Title: Perinatal and 2 year neurodevelopmental outcome in late preterm fetal compromise: the TRUFFLE 2 Randomised Trial
Funder: Department of Health and Social Care

Abstract: Background:_x000D_ In the last months of pregnancy, babies who are smaller or who grow more slowly than expected are at higher risk of dying in the mother's womb. Some of these smaller babies who survive may have developmental problems later in infancy. Doctors have many ways to monitor such babies in the womb but, until the baby is born, the only treatment available is to deliver the baby._x000D_ If the pregnancy has reached its full term, induction of labour is the usual option. If the baby is preterm (before 37 weeks of pregnancy) the right course of action is less clear. Delivering the baby early, as soon as there are signs of problems, will minimise any damage due to lack of oxygen in the womb, but the baby may suffer harm as a result of being born prematurely. This study is looking at the balance of risks linked with continuing the pregnancy a little longer or delivering the baby early._x000D_ What will happen?_x000D_ Pregnant women whose babies are either smaller or growing more slowly than expected between 32 and 36 weeks of pregnancy, will be invited to participate in the study. Their babies will be closely monitored with ultrasound scans, Doppler tests for blood flow and computerised heart rate tests. All these tests are regularly used in normal maternity care and are safe. If the Doppler test shows changes in the blood flow to the baby’s brain, mothers will be randomly assigned to one of two groups: in one group the babies will be delivered immediately. In the other group the babies will continue to be monitored closely. Babies in the second group will be delivered if computerised analysis of the baby’s heart rate shows signs of deteriorating health. The health of all the babies will be recorded at birth, and their development checked at two years of age._x000D_ Why is this study important?_x000D_ Two studies have compared delivering babies at the first sign of concern or waiting for longer. They showed no difference between the two policies. However, the studies looked at relatively small numbers of pregnant women the tests used to identify babies at increased risk are now considered old fashioned. Modern tests of brain blood flow are much better, but it is important to see if these tests can indeed identify babies who would benefit from an early delivery._x000D_ Patient and Public Involvement (PPI)_x000D_ Sands, the stillbirth and neonatal death charity, is the main stillbirth support charity in the UK and has been closely involved in the development and design of TRUFFLE 2 RCT. Senior SANDS Research Members (Charlotte Bevan and Laura Price) took part in TRUFFLE meetings in Naples 2016 and Berlin 2017. Sands is clear that there is an urgent need for better assessment and care of women and their babies in late pregnancy and supports the study._x000D_ The topic of this trial has also been prioritised by the Royal college of Obstetrics and Gynaecology’s (RCOG) Stillbirth Clinical Studies Group, and addresses three of the James Lind Alliance (JLA) Stillbirth Priority Setting Partnership’s priorities. The study is closely aligned with the NHS ‘Saving Babies’ Lives Care Bundle’, one of whose four key components is detection of fetal growth restriction . The study also has support from patient groups aligned with the European TRUFFLE centres . As part of the Feasibility Study (www.truffle-study.org), 14 women commented on the objectives of the trial as a pilot in one centre. All supported the objectives and 12/14 would consider participation.

Lay abstract: Background: We propose a randomised controlled study of the timing of delivery in late onset fetal growth restriction. There is little consensus on which fetal monitoring modalities should trigger delivery. The consequences of inappropriately early-or late delivery for perinatal and infant health, & maternal morbidity, are potentially enormous. Current interest lies in the use of cerebral Doppler indices in timing delivery to optimize fetal outcomes, though little evidence exists._x000D_ Design: Two arm open label randomised controlled multicentre trial _x000D_ Setting: Eight consultant led maternity units in the UK & 24 in Europe_x000D_ Target Population: Women with singleton pregnancies 32 to 36+6 weeks in whom the fetal abdominal circumference is <10th percentile or has crossed 50 percentiles since ultrasound scan at 18-22 weeks._x000D_ Health Technologies assessed: Middle cerebral artery Doppler & umbilical artery Doppler expressed as a ratio. Fetal heart rate abnormalities on computerised cardiotocograph. Both used as the trigger for delivery._x000D_ Randomisation: Immediate delivery or conservative management in a 1:1 ratio based on cerebral Doppler ratio exceeding a predefined value, graduated as requiring most severe changes at earlier gestation._x000D_ Outcomes: Primary outcome is short term composite of fetal/neonatal outcome which comprises mortality; or need for respiratory support on first neonatal day; or, serious morbidity, with secondary outcome being neurodevelopmental attainment at 2 years using the PARCA-R questionnaire._x000D_ Sample Size: The trial is powered to detect if delivery following cerebral redistribution (intervention arm) is superior to conservative management following cerebral redistribution (control arm) on this outcome. A difference in primary outcome from 15% (control arm) to 9% (intervention arm) demonstrates an odds ratio of 0.560. At 5% significance with 95.5% power, 780 participants per arm are required, giving 1558 in total. After the 2 year follow-up, we will analyse questionnaire results using a non-inferiority framework with an equivalence margin of 8 points on the PARCA-R measure scale and a common standard deviation of 33.5. At 2-sided 5% significance level and with 615 patients per arm given approximately 21% loss to follow-up for the two-year outcome, this provides a power of 98.7%_x000D_ Analysis: Primary analyses will be undertaken after database lock following 2 year data collection. No interim analyses are planned., though safety data will be reviewed quarterly. We will test if two-level models are required, due to clustering by hospital, and fit a single-level model if this is not needed. Missing primary outcome data are accounted for in sensitivity analyses using multiple imputation assuming that data are missing at random._x000D_ Trial milestones: Study set up 0-6 months; recruitment/randomization 7-30 months, with recruitment review decision at 18 months; 2 year questionnaires 31-54 months; analyses/writing up/dissemination 55-60 months. This equates to 5 years (60 months)._x000D_ Team Expertise: The TRUFFLE group is a mature UK based European group of obstetricians, fetal medicine experts, neonatologists, triallists, statistician, neurodevelopmental follow up experts & PPI representatives that have delivered a multicentre RCT on early fetal growth restriction (2005-10) and a feasibility study (2017-18).

Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH