The Fetal Growth Restriction at Term Managed by Angiogenic Factors Versus Feto-Maternal Doppler (GRAFD) Trial to Avoid Adverse Perinatal Outcomes: Protocol for a Multicenter, Open-Label, Randomized Controlled Trial

Abstract

Background Fetal smallness affects 10% of pregnancies. Small fetuses are at a higher risk of adverse outcomes. Their management using estimated fetal weight and feto-maternal Doppler has a high sensitivity for adverse outcomes; however, more than 60% of fetuses are electively delivered at 37 to 38 weeks. On the other hand, classification using angiogenic factors seems to have a lower false-positive rate. Here, we present a protocol for the Fetal Growth Restriction at Term Managed by Angiogenic Factors Versus Feto-Maternal Doppler (GRAFD) trial, which compares the use of angiogenic factors and Doppler to manage small fetuses at term. Objective The primary objective is to demonstrate that classification based on angiogenic factors is not inferior to estimated fetal weight and Doppler at detecting fetuses at risk of adverse perinatal outcomes. Methods This is a multicenter, open-label, randomized controlled trial conducted in 20 hospitals across Spain. A total of 1030 singleton pregnancies with an estimated fetal weight ≤10th percentile at 36+0 to 37+6 weeks+days 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 ≥38 will be classified as having fetal growth restriction; otherwise, they will be classified as being small for gestational age. In both arms, the fetal growth restriction group will be delivered at ≥37 weeks and the small for gestational age group at ≥40 weeks. We will assess differences between the groups by calculating the relative risk, the absolute difference between incidences, and their 95% CIs. Results Recruitment for this study started on September 28, 2020. The study results are expected to be published in peer-reviewed journals and disseminated at international conferences in early 2023. Conclusions The angiogenic factor–based protocol may reduce the number of pregnancies classified as having fetal growth restriction 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. Trial Registration ClinicalTrials.gov NCT04502823; https://clinicaltrials.gov/ct2/show/NCT04502823 International Registered Report Identifier (IRRID) DERR1-10.2196/37452

Prognostic value of angiogenic markers in pregnancy with fetal growth restriction

“…In recent years, it has been shown that angiogenic imbalance is present in pregnancies with FGR combined with pre-eclampsia, as well as in those with FGR alone, while the imbalance is greater in patients with co-existing pre-eclampsia 18,23,28,29 . Increased sFlt-1/PlGF ratio has been shown to be predictive of adverse outcome and shorter time to delivery in early-onset SGA and FGR 7,20,21,30 and has been suggested as a potential additive tool for fetal surveillance in these patients 20,22 . Various studies have demonstrated the value of the sFlt-1/PlGF ratio in the management of pregnancies complicated by FGR, showing an association between increased maternal serum sFlt-1/PlGF values and shorter time to delivery as well as higher rates of adverse perinatal outcome 7,21,31,32 .…”

“…Increased sFlt-1/PlGF ratio has been shown to be predictive of adverse outcome and shorter time to delivery in early-onset SGA and FGR 7,20,21,30 and has been suggested as a potential additive tool for fetal surveillance in these patients 20,22 . Various studies have demonstrated the value of the sFlt-1/PlGF ratio in the management of pregnancies complicated by FGR, showing an association between increased maternal serum sFlt-1/PlGF values and shorter time to delivery as well as higher rates of adverse perinatal outcome 7,21,31,32 . Bonacina et al 22 confirmed the high predictive performance of angiogenic markers for fetal distress, and proposed incorporating assessment of the sFlt-1/PlGF ratio into surveillance protocols for pregnancies with FGR.…”

“…Imbalance between the angiogenic biomarkers soluble fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF), characterized by an increased sFlt-1/PlGF ratio, is thought to play an important role in the development of placental dysfunction and related diseases, such as pre-eclampsia [16][17][18][19] and FGR 18,20 . Increased maternal serum sFlt-1/PlGF ratio has also been shown to be predictive of adverse perinatal outcome and shorter time to delivery in early-onset small-for-gestational-age (SGA) and FGR fetuses 7,20,21 , and has been suggested as a potential additive tool for fetal surveillance in these patients 20,22 .…”