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.
12 / 2005 - unknown
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. No effective treatment for fetal growth restriction is available. Obstetric management is aimed at fetal surveillance and timely delivery to prevent fetal damage or death by asphyxia, acidosis or malnutrition. When fetal growth restriction occurs at an early gestational age the considerable risk of preterm delivery has to be balanced carefully against the risk of allowing pregnancy to continue. In the Netherlands (and the rest of Europe), fetal surveillance is generally performed by fetal heart rate monitoring and Doppler ultrasound measurement of the umbilical artery. Unfortunately, the accuracy of these techniques is restricted and obstetricians are often uncertain regarding the optimum time of delivery. The proposed pathophysiology of severe fetal growth restriction is that vascular supply to the uterus and placenta is insufficient, as manifested by abnormal uterine artery Doppler velocimetry. Malnutrition and later fetal hypoxia trigger compensatory haemodynamic changes, which include redistribution of blood flow to essential organs (brain, heart) at the expense of other organ systems (kidney, lungs, intestines). This compensatory mechanism can be recognised by an increase in pulsatility index in the umbilical artery and a decrease in the middle cerebral artery or coronary artery. The duration of this compensatory phase can last weeks and appears not to have deleterious short term consequences. Ultimately, hypoxaemia and acidosis will result in myocardial and cerebral dysfunction, followed by death. The objective is to determine if timing delivery based on changes of fetal haemodynamic modifications monitored by venous Doppler velocimetry, where they precede a non-reassuring FHR pattern, is more effective than using computerised FHR monitoring. The endpoint of the study is healthy survival documented by a normal Griffith`s Mental Developmental Scale at two years corrected age and absence of sensory or motor disabilities. Fetal growth restriction necessitating delivery before 32 weeks occurs in 0.3%-0.4% of pregnancies. Although the absolute number of affected pregnancies is low (600-800/year in the Netherlands), surveillance of these patients is time consuming and complicated. The following data concerning women, who were hospitalised because of fetal growth restriction between 26 and 32 weeks, are from the AMC perinatal database 2000-2003. Mean duration of antenatal admission was 9 days (median 5, range 0-85). In some active treatment was abandoned after discussion with the parents, because chances for healthy survival of the infant were estimated low. All remaining infants were delivered by caesarean section. Mean duration of neonatal intensive care was 26 days (median 20, range 1-131). Neonatal mortality was 13%. Further health costs in this group are considerable due to the high incidence of later disabilities or handicaps (10%), and learning (30%) or behavioural (43%) disturbances [9,10]. Only approximately 50% of the infants are expected to develop normally. Preliminary studies Between 1999 and 2000 an observational study to compare venous Doppler measurements with electronic calculation of fetal heart short-term variability was performed by a part of the European project group and described in two manuscripts.[1,4]