Background Fetal growth restriction (FGR) is a serious obstetric condition for which there is currently no treatment. to 2?years of corrected age in surviving infants. Standardised longitudinal ultrasound measurements are performed, including: fetal biometry; uterine artery, umbilical artery, middle cerebral artery, and ductus venosus Doppler velocimetry; and uterine artery and umbilical vein volume blood flow. Samples of maternal blood and urine, amniotic fluid (if amniocentesis performed), placenta, umbilical cord blood, and placental bed (if caesarean delivery performed) are collected for bio-banking. An initial analysis of maternal blood samples at enrolment is usually planned to identify biochemical markers that are predictors for fetal or neonatal death. Discussion The findings of the EVERREST Prospective Study will support the development of a novel therapy for severe early onset FGR by describing in detail the natural history of the disease and by identifying women whose pregnancies have the poorest outcomes, in whom a therapy might be most advantageous. The findings will also enable better counselling of couples with affected pregnancies, and provide a valuable resource for future research into the causes of FGR. Trial registration “type”:”clinical-trial”,”attrs”:”text”:”NCT02097667″,”term_id”:”NCT02097667″NCT02097667 registered 31st October 2013. Electronic supplementary material The online version of this article (doi:10.1186/s12884-017-1226-7) contains supplementary material, which is available to authorized users. Keywords: Fetal growth restriction, Prospective cohort, Ultrasound biometry, Doppler ultrasound, Angiogenic, Prediction, Outcome, Uteroplacental, Placental insufficiency Background Fetal growth restriction (FGR) is usually a serious condition affecting about 8% of all pregnancies and contributing to 30% of stillbirths [1]. As 210344-95-9 supplier yet there is no therapy that enhances fetal growth in utero, thus current management is usually to deliver the fetus before intrauterine death or irreversible organ damage occurs [2]. This is particularly challenging in early onset FGR, where delivery adds additional risks to the baby from extremely preterm birth, with its own attendant short and long-term complications [3C5]. Furthermore FGR may be detected when the estimated fetal weight (EFW) is usually below 500?g, a situation considered by many to be nonviable. Npy FGR is usually most commonly due to three principal factors: a) maternal diseases such as infections; b) fetal chromosomal, genetic, or structural anomalies; and, most often, c) placental insufficiency. Placental insufficiency manifests as inadequate uteroplacental blood flow on ultrasound scan and maternal vascular malperfusion (MVM) on placental histology [6]. We are currently developing a treatment for FGR caused by placental insufficiency [orphan designation EU/3/14/1415], using maternal adenovirus gene therapy to increase expression of vascular endothelial growth factor (VEGF) protein in the uterine arteries. VEGF is usually secreted by the placenta, induces vasodilatation, and mediates vasculogenesis and angiogenesis [7, 8]. In FGR, however, maternal serum levels of VEGF are significantly lower than 210344-95-9 supplier in normal pregnancy [9, 10]. Previous studies in normal sheep pregnancy show that administering adenovirus VEGF gene therapy (Ad.VEGF) into the maternal uterine arteries raises uterine artery blood volume circulation long-term, causes nitric oxide release and relaxes the vessels [11C13]. Further studies in sheep and guinea pig models of FGR have shown that administering Ad. VEGF gene therapy into the maternal uterine arteries safely raises fetal growth [14, 15]. The EVERREST Consortium plans to carry out a phase I/IIa trial to assess the security and efficacy of maternal uterine artery injection of Ad.VEGF in women with pregnancies affected by severe early onset FGR. This will be called the EVERREST Clinical Trial. For the first-in-woman trial of maternal gene therapy the eligibility criteria will be designed to identify severely affected pregnancies, where the balance of risk and potential benefit is usually most favourable. These pregnancies will naturally have high rates of maternal, fetal, and neonatal complications. The security and efficacy of the intervention in the trial pregnancies will need to be compared with data from a cohort of similar severely affected pregnancies that do not undergo intervention. Several prospective cohort studies have investigated the outcomes of pregnancies where the fetus was found to be 210344-95-9 supplier small in mid-pregnancy [16C21]. Recent outcome data have also been provided by the Trial of Umbilical and Fetal Flow in Europe (TRUFFLE), a randomised controlled.