Management of fetal Growth Restriction at term by Angiogenic Factors versus feto-maternal Doppler (GRAFD) to avoid adverse perinatal outcomes: multicenter open-label randomized controlled trial study protocol (Preprint)

BACKGROUND Fetal smallness affects 10% of pregnancies. These fetuses are at a higher risk of adverse outcomes. Their management using estimated fetal weight (EFW) and feto-maternal Doppler has a high sensitivity for adverse outcomes; however, more than 60% of fetuses are electively delivered at 37-38 weeks. On the other hand, the classification using angiogenic factors (AF) seems to have a lower false positive rate. Here we present a protocol for the GRAFD trial, which compares the management of small fetuses at term using AF or Doppler. OBJECTIVE The primary objective is to demonstrate that classification based on AF is not inferior to EFW and Doppler to detect fetuses at risk of adverse perinatal outcomes. METHODS This is a multicentre, open-label, randomized controlled trial conducted in 20 hospitals across Spain. A total of 1,030 singleton pregnancies with an EFW ≤10th percentile at 36+0 to 37+6 weeks will be recruited and randomly allocated to either the control or the intervention group. In the control group, standard Doppler-based management will be used. In the intervention group, cases with a soluble fms-like tyrosine kinase to placental growth factor ratio (sFlt-1/PlGF) ≥38 will be classified as fetal growth restriction (FGR), otherwise as small for gestational age (SGA). In both arms, FGR will be delivered at ≥37 weeks and SGA at ≥40 weeks. We will assess the differences between groups calculating the relative risks (RR) and their 95% confidence intervals. RESULTS The study is in the recruitment and data collection phase. The study results are expected to be published in peer-reviewed journals and disseminated at international conferences by the end of 2022 or in early 2023. CONCLUSIONS The AF-based protocol may reduce the number of pregnancies with classified as FGR without worsening perinatal outcomes. Moreover, reducing the number of unnecessary labor inductions would reduce costs and the risks derived from possible iatrogenic complications. Additionally, fewer inductions would lower the rate of early-term neonates, thus improving neonatal outcomes and potentially reducing long-term infant morbidities. CLINICALTRIAL NCT04502823