A large European trial will test whether delivering babies early, based on a specific brain blood-flow measurement, improves outcomes for growth-restricted fetuses between 32 and 36 weeks of pregnancy. Doctors currently lack clear evidence on when to deliver these late preterm babies. Growth restriction in the womb raises risks of stillbirth, neonatal complications, and long-term developmental problems. But delivering too early also carries serious risks from prematurity. The trial compares immediate delivery against waiting, using a Doppler ultrasound ratio of blood flow in the middle cerebral and umbilical arteries as the trigger. The primary outcome is a composite of death, need for breathing support at birth, or serious illness. A secondary outcome measures neurodevelopment at age two using a standardised questionnaire. If the intervention arm proves superior, it would give obstetricians a concrete, evidence-based threshold for timing delivery in late fetal growth restriction—a condition affecting roughly 5–10% of pregnancies. This could reduce neonatal intensive care admissions, prevent avoidable stillbirths, and improve long-term cognitive outcomes for thousands of children each year, without requiring expensive new technology. The trial is powered to detect a reduction in the primary outcome from 15% to 9%, requiring 1,558 participants across 32 maternity units in the UK and Europe.
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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. Design: Two arm open label randomised controlled multicentre trial Setting: Eight consultant led maternity units in the UK & 24 in Europe 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. 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. 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. 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. 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% 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. 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). 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).
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