JMIR RESEARCH PROTOCOLS Garcia-Manau et al Protocol 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 Pablo Garcia-Manau1*, MD; Manel Mendoza1*, MD, PhD; Erika Bonacina1, MD; Raquel Martin-Alonso2,3, MD; Lourdes Martin4, MD; Ana Palacios5,6, MD, PhD; Maria Luisa Sanchez7, MD; Cristina Lesmes8, MD, PhD; Ivan Hurtado9, MD; Esther Perez10, MD; Albert Tubau11, MD; Patricia Ibañez12, MD; Marina Alcoz13, MD; Nuria Valiño14, MD, PhD; Elena Moreno15, MD; Carlota Borrero16, MD, PhD; Esperanza Garcia17, MD; Eva Lopez-Quesada18, MD, PhD; Sonia Diaz19, MD; Jose Roman Broullon20, MD, PhD; Mireia Teixidor21, MD; Carolina Chulilla22, MD; Maria M Gil2,3, MD, PhD; Monica Lopez4, MD; Amparo Candela-Hidalgo5,6, MD; Andrea Salinas-Amoros7, MD; Anna Moreno8, MD; Francesca Morra9, MD; Oscar Vaquerizo10, MD; Beatriz Soriano11, MD; Marta Fabre12, MD; Elena Gomez-Valencia13, MD; Ana Cuiña14, MD; Nicolas Alayon15, MD; Jose Antonio Sainz16, MD, PhD; Angels Vives17, MD; Esther Esteve18, MD; Vanesa Ocaña19, MD; Miguel Ángel López20, MD, PhD; Anna Maroto21, MD, PhD; Elena Carreras1, MD, PhD 1 Maternal Fetal Medicine Unit, Department of Obstetrics, Vall d’Hebron Barcelona Hospital Campus, Universitat Autònoma de Barcelona, Barcelona, Spain 2 Maternal Fetal Medicine Unit, Department of Obstetrics, Hospital Universitario de Torrejón, Madrid, Spain 3 School of Medicine, Universidad Francisco de Vitoria, Madrid, Spain 4 Maternal Fetal Medicine Unit, Department of Obstetrics, Hospital Universitari de Tarragona Joan XXIII, Universitat Rovira i Virgili, Tarragona, Spain 5 Department of Obstetrics, Alicante University General Hospital, Miguel Hernandez University, Alicante, Spain 6 Alicante Institute for Health and Biomedical Research, Alicante, Spain 7 Maternal Fetal Medicine Unit, Department of Obstetrics, Hospital Clínico Universitario Virgen de la Arrixaca, Universidad de Murcia, Murcia, Spain 8 Maternal Fetal Medicine Unit, Department of Obstetrics, Parc Taulí Hospital Universitari, Universitat Autònoma de Barcelona, Sabadell, Spain 9 Maternal Fetal Medicine Unit, Department of Obstetrics, Hospital Universitari Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain 10 Maternal Fetal Medicine Unit, Department of Obstetrics, Hospital Universitario de Cabueñes, Universidad de Oviedo, Gijón, Spain 11 Maternal Fetal Medicine Unit, Department of Obstetrics, Hospital Universitari Son Llàtzer, Universitat de les Illes Balears, Palma de Mallorca, Spain 12 Aragon Institute for Health Research, Department of Obstetrics, Hospital Clínico Universitario Lozano Blesa, Zaragoza, Spain 13 Maternal Fetal Medicine Unit, Department of Obstetrics, Fundació Althaia, Universitat de Vic, Manresa, Spain 14 Maternal Fetal Medicine Unit, Department of Obstetrics, Hospital Universitario de A Coruña, Universidade da Coruña, A Coruña, Spain 15 Maternal Fetal Medicine Unit, Department of Obstetrics, Hospital General Universitario de Elche, Universidad Miguel Hernández, Elche, Spain 16 Maternal Fetal Medicine Unit, Department of Obstetrics, Hospital Universitario Virgen de Valme, Universidad de Sevilla, Sevilla, Spain 17 Maternal Fetal Medicine Unit, Department of Obstetrics, Consorci Sanitari de Terrassa, Universitat Internacional de Catalunya, Terrassa, Spain 18 Maternal Fetal Medicine Unit, Department of Obstetrics, Hospital Universitari Mútua Terrassa, Universitat de Barcelona, Terrassa, Spain 19 Maternal Fetal Medicine Unit, Department of Obstetrics, Hospital Universitario de Getafe, Universidad Europea de Madrid, Getafe, Spain 20 Maternal Fetal Medicine Unit, Department of Obstetrics, Hospital Universitario Puerta del Mar, Universidad de Cádiz, Cádiz, Spain 21 Maternal Fetal Medicine Unit, Department of Obstetrics, Hospital Universitari de Girona Doctor Josep Trueta, Universitat de Girona, Girona, Spain 22 Maternal Fetal Medicine Unit, Department of Obstetrics, Hospital Universitario Nuestra Señora de Candelaria, Universidad de La Laguna, Santa Cruz de Tenerife, Spain * these authors contributed equally Corresponding Author: Manel Mendoza, MD, PhD Maternal Fetal Medicine Unit, Department of Obstetrics Vall d’Hebron Barcelona Hospital Campus Universitat Autònoma de Barcelona https://www.researchprotocols.org/2022/10/e37452 JMIR Res Protoc 2022 | vol. 11 | iss. 10 | e37452 | p. 1 (page number not for citation purposes) XSL• FO RenderX JMIR RESEARCH PROTOCOLS Garcia-Manau et al Passeig de la Vall d’Hebron, 119-129 Barcelona, 08035 Spain Phone: 34 934893085 Email: manel.mendoza@vallhebron.cat 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 (JMIR Res Protoc 2022;11(10):e37452) doi: 10.2196/37452 KEYWORDS fetal growth restriction; small for gestational age; PlGF; sFlt-1; Doppler; angiogenic factors Moreover, the severity of fetal smallness is usually classified Introduction into 2 categories: fetal growth restriction (FGR), which is Background defined as a fetus failing to reach its genetically predetermined growth potential, and small for gestational age (SGA), which Fetal smallness affects around 10% of pregnancies [1]. Small is defined as a fetus being small but without an increased risk fetuses are at a higher risk of intrauterine death and adverse of adverse perinatal outcomes. SGA fetuses are commonly perinatal outcomes [2]. In order to prevent these adverse referred to as constitutionally small fetuses [1,8]. Several criteria outcomes, identification and appropriate management of small based on Doppler studies, growth velocity, and biometric fetuses are crucial [3,4]. Based on gestational age (<32 weeks percentiles are available to discriminate between SGA and FGR of gestation versus ≥32 weeks of gestation) at the time of disease fetuses [2,8,9]. One of the most widely used classifications, as onset, 2 distinct patterns of severity are observed in small well as the one used in most maternity wards in Spain, is the fetuses, with the more severe cases being those with onset early one proposed by Figueras and Gratacós [8]. This classification, in pregnancy (<32 weeks of gestation) [5]. In these cases, based on estimated fetal weight (EFW) and feto-maternal management is mainly based on fetal Doppler and indications Doppler, allows the identification of the subset of small fetuses for delivery are quite consistent [2], generally resulting in at a greater risk of perinatal complications (ie, true FGR fetuses) preterm neonates. However, most cases are diagnosed at a later and the subset of small fetuses with a risk of perinatal gestational age (≥32 weeks) and, in this particular context, there complications similar to that of a normally growing fetus (ie, is no clear consensus on the appropriate interventions to prevent constitutionally small or SGA fetuses). According to several adverse perinatal outcomes [6-8]. guidelines, FGR fetuses may benefit from early-term elective delivery (at 37-38 weeks), while SGA fetuses require closer https://www.researchprotocols.org/2022/10/e37452 JMIR Res Protoc 2022 | vol. 11 | iss. 10 | e37452 | p. 2 (page number not for citation purposes) XSL• FO RenderX JMIR RESEARCH PROTOCOLS Garcia-Manau et al monitoring, but not elective delivery until full term (39-40 perinatal outcomes as compared to the expectant management weeks). FGR/SGA classification based on Doppler and EFW group. percentiles has a high sensitivity for adverse perinatal outcomes; nevertheless, more than 60% of fetuses with an EFW below the Management of SGA: Feto-Maternal Doppler 10th percentile are classified as FGR and, therefore, will be In recent years, and after the publication of DIGITAT, several delivered at 37 to 38 weeks [8]. Neonates delivered at 37+0 to studies have evaluated the role of feto-maternal circulation 38+6 weeks+days of gestation are considered early-term and assessment by Doppler ultrasound in small fetuses [25-28]. have poorer neonatal outcomes than full-term neonates (≥39 These studies have shown that Doppler assessment allows weeks of gestation) [10-12]. For this reason, early-term elective identifying the subset of small fetuses at a higher risk of adverse delivery should be restricted to FGR fetuses at an actual risk perinatal outcomes (ie, those with FGR). Historically, umbilical for adverse outcomes. artery (UA) pulsatility index (PI) assessed with Doppler has been considered the standard parameter to identify FGR. Placental Insufficiency and SGA/FGR However, a large proportion of small fetuses with normal UA The precise pathophysiology of SGA/FGR is unknown, but PI (ie, <95th percentile) have poorer perinatal outcomes than placental insufficiency is a common finding [13,14]. Several normally growing fetuses [21,29,30]. Thus, UA PI alone cannot studies have reported histopathological findings related to be used to discriminate SGA from FGR fetuses [1,29]. Further placental malperfusion in SGA and FGR pregnancies [15,16]. studies showed that other Doppler parameters might have a The severity of the underlying placental insufficiency can be greater predictive ability for adverse outcomes in late-onset assessed by Doppler of the feto-maternal circulation [15,17]. SGA and FGR: cerebroplacental ratio (CPR), middle cerebral Some studies have also shown an association between placental artery (MCA) PI, and uterine artery (UtA) PI [1,26,31,32]. findings consistent with maternal vascular malperfusion and According to these studies, abnormal CPR (ie, <5th percentile), angiogenic imbalance involving a decrease of placental growth MCA PI (ie, <5th percentile), or UtA PI (ie, >95th percentile) factor (PlGF), a proangiogenic factor, and an increase in soluble may be able to identify small fetuses at a higher risk of adverse fms-like tyrosine kinase-1 (sFlt-1), an antiangiogenic factor, outcomes (ie, FGR). A study including these criteria showed resulting in an increased sFlt-1/PlGF ratio [18-20]. that small fetuses with abnormal Doppler parameters accounted for 60% of all small fetuses, indicating that more than half of Management of SGA/FGR Pregnancies: EFW fetuses with an EFW below the 10th percentile would be As is widely known, there is an inversely proportional classified as FGR and that according to our current protocol, relationship between EFW and the risk of adverse perinatal early-term induction of labor would therefore be recommended outcomes [21-23]. For this reason, in DIGITAT [25]. In the earlier study, induction of labor was recommended (Disproportionate Intrauterine Growth Intervention Trial At at 37 weeks of gestation in FGR fetuses (small fetuses with an Term), the only clinical trial ever conducted to evaluate the role EFW below the 3rd percentile or with an EFW below the 10th of early-term elective delivery in improving perinatal outcomes percentile accompanied by the presence of any abnormal of small fetuses, the only inclusion criterion was an EFW below Doppler parameter), while for other pregnancies with an EFW the 10th percentile [24]. In that study, fetuses with an EFW below the 10th percentile (ie, SGA fetuses) induction of labor below the 10th percentile were randomized into two groups: was recommended at 40 weeks. Following that protocol, 134 (1) early-term induction of labor and (2) expectant management cases (26.3%) had an adverse outcome, including, until the onset of spontaneous labor. Perinatal outcomes were nonexclusively, 46 cases of neonatal acidosis and 106 cases of compared between the groups, showing that systematic emergency cesarean delivery due to nonreassuring early-term labor induction in pregnancies with small fetuses cardiotocography (CTG). Neonatal acidosis in that study was did not improve perinatal outcomes. By contrast, there was a defined as a UA pH below 7.15 and a base excess greater than significant increase in the number of admissions to the neonatal –12 mEq/L. intensive care unit (NICU) and intermediate care unit for early-term neonates (51.1%) as compared to full-term neonates Management of SGA: Angiogenic Factors (39.8%). Since no differences were found in the baseline To date, few studies have evaluated the usefulness of angiogenic characteristics of the groups at enrollment, it is fair to assume factors (AFs) in the management of late-onset or term SGA/FGR that this 11.3% difference in neonatal admissions was mainly pregnancies. These studies show that the higher the sFlt-1/PlGF due to differences in gestational age at delivery between the ratio, the worse the prognosis for small fetuses and the greater groups. For this reason, a Cochrane review in 2015 [7] the risk of developing preeclampsia (PE), which in turn worsens concluded that there is no evidence suggesting that early-term maternal prognosis [19,33-35]. Recently, a large observational elective delivery of small fetuses (based only on EFW) should study compared the identification of term (36+0 to 37+6 be recommended to avoid adverse perinatal outcomes. It must weeks+days) small fetuses (EFW below the 10th percentile) at be noted that in DIGITAT, other factors predictive of poor a higher risk of adverse outcomes using the standard Doppler prognosis in small fetuses, such as the amount of amniotic fluid, assessment versus a new approach based on AFs [36]. In that feto-maternal Doppler, or biophysical profile score, were not study, 521 fetuses were identified as small, of which 102 had taken into account. Therefore, it might be possible that with abnormal AF values (sFlt-1/PlGF ratio ≥38), whereas 412 had more accurate identification of small fetuses who are actually abnormal Doppler parameters. Therefore, according to the at a higher risk of perinatal complications (ie, those with FGR), Doppler-based protocol, 79.1% (412/521) of small fetuses would early-term elective delivery would have been found to improve have been classified as FGR, whereas according to the new https://www.researchprotocols.org/2022/10/e37452 JMIR Res Protoc 2022 | vol. 11 | iss. 10 | e37452 | p. 3 (page number not for citation purposes) XSL• FO RenderX JMIR RESEARCH PROTOCOLS Garcia-Manau et al AF-based approach, only 19.6% (102/521) of small fetuses Objectives would have been classified as FGR. By contrast, both approaches had a similar negative predictive value for adverse Primary Objective perinatal outcomes (99.3% and 99%, respectively), indicating To determine whether the classification of small fetuses as FGR a good, similar prognosis for those pregnancies not classified or SGA based on AFs is not inferior to the standard clinical as FGR regardless of the classification used. Therefore, approach (based on EFW and Doppler percentiles) for the classification based on AFs seems more accurate and may have identification of fetuses at a higher risk of adverse perinatal a lower rate of false positives than the Doppler-based protocol outcomes (neonatal acidosis and cesarean section due to for the identification of small fetuses at a higher risk of adverse nonreassuring CTG). outcomes. Secondary Objectives Early-term Delivery: Short-term and Long-term To determine whether (1) the lower false-positive rate using Consequences AFs instead of Doppler to identify small fetuses as FGR results It might seem that whether a delivery is early term (<39 weeks) in a reduced number of elective deliveries before 38, 39, and or full term (≥39 weeks) is not very relevant in terms of postnatal 40 weeks, (2) a lower rate of early-term elective deliveries prognosis. However, several studies have found increased results in a reduced number of deliveries (elective and immediate postnatal morbidity (such as admission to the NICU spontaneous) before 38, 39, and 40 weeks, (3) a lower rate of due to a need for respiratory support) [10] and poorer long-term early-term elective deliveries results in a reduced number of outcomes, such as the development of diabetes, obesity, and cesarean deliveries, (4) a lower rate of early-term elective respiratory morbidity, in infants born early term as compared deliveries results in a reduced number of neonatal admissions to full term [11,12]. Thus, a reduction in the number of elective to the NICU and a lower rate of adverse perinatal outcomes, (5) early-term deliveries due to FGR overdiagnosis would certainly the AF-based approach reduces PE incidence in pregnancies lead to improved short-term and long-term postnatal outcomes, with small fetuses, and (6) the AF-based classification reduces ultimately resulting in healthier infants and adults. the incidence of placental-related complications. Rationale for the Study Methods The most common protocols used worldwide for the management of late-onset SGA/FGR are based on Doppler Study Setting assessment, which recommends elective delivery at 37 weeks The study will be conducted in 20 hospitals across Spain with (or even earlier) in FGR pregnancies [25,37,38]. According to experience in managing term SGA/FGR pregnancies: Vall a classification based on Doppler parameters and EFW d’Hebron Barcelona Hospital Campus (Barcelona), Hospital percentiles, up to 79.1% of small fetuses would be classified as Universitario de Torrejón (Torrejón de Ardoz), Hospital FGR. By contrast, when using the AF-based approach Universitari de Tarragona Joan XXIII (Tarragona), Hospital (sFlt-1/PlGF ≥38), only 19.6% of small fetuses would be General Universitario de Alicante (Alicante), Hospital Clínico classified as FGR [36]. Additionally, both approaches seem to Universitario Virgen de la Arrixaca (Murcia), Parc Taulí have a similar ability to identify small fetuses at risk (ie, those Hospital Universitari (Sabadell), Hospital Universitari Germans with FGR), which may benefit from an earlier elective delivery. Trias i Pujol (Badalona), Hospital Universitario de Cabueñes Therefore, the AF-based protocol may potentially reduce by up (Gijón), Hospital Universitari Son Llàtzer (Palma de Mallorca), to 75.2% (from 79.1% to 19.6%) the number of pregnancies Hospital Clínico Universitario Lozano Blesa (Zaragoza), classified as FGR (in which labor would be induced at 37 weeks) Fundació Althaia (Manresa), Hospital Universitario de A Coruña without worsening perinatal outcomes. Moreover, reducing the (A Coruña), Hospital General Universitario de Elche (Elche), number of unnecessary labor inductions would not only improve Hospital Universitario Virgen de Valme (Sevilla), Consorci patients’ perception of medical attention, but also would reduce Sanitari de Terrassa (Terrassa), Hospital Universitari Mútua the costs and risks derived from possible iatrogenic Terrassa (Terrassa), Hospital Universitario de Getafe (Getafe), complications, which in turn would reduce the rate of cesarean Hospital Universitario Puerta del Mar (Cádiz), Hospital deliveries. Additionally, fewer inductions would lower the rate Universitari de Girona Doctor Josep Trueta (Girona), and of early-term neonates, thus improving neonatal outcomes and Hospital Universitario Nuestra Señora de Candelaria (Santa potentially reducing long-term infant metabolic, endocrine, and Cruz de Tenerife). respiratory morbidities. Trial Design The sFlt-1/PlGF ratio has been shown to accurately predict PE This is a multicenter, open-label, randomized clinical trial. The and associated complications several weeks before onset study design adheres to the SPIRIT (Standard Protocol Items: [39-42]. Therefore, a management protocol based on AFs may Recommendations for Interventional Trials) quality standard potentially reduce the rate of PE and other maternal criteria for randomized trials [43]. A pragmatic approach will complications associated with PE, such as placental abruption be adopted in order to evaluate the effectiveness of the or eclampsia. intervention in real-life, routine practice conditions. Therefore, each participating site will use the fetal growth charts, Doppler reference values, and methods for cervical ripening and labor induction usually applied in their clinical practice. https://www.researchprotocols.org/2022/10/e37452 JMIR Res Protoc 2022 | vol. 11 | iss. 10 | e37452 | p. 4 (page number not for citation purposes) XSL• FO RenderX JMIR RESEARCH PROTOCOLS Garcia-Manau et al The clinical trial was entered in the ClinicalTrials.org registry The remaining cases will be classified as SGA. In the on August 6, 2020 (NCT04502823). intervention group, the UA PI, MCA PI, CPR, and UtA PI percentiles will be concealed to obstetricians in order to avoid Inclusion Criteria any influence that this information might have on their Inclusion criteria at the time of enrollment are as follows: (1) interpretation of fetal movements or CTG. age at least 16 years, (2) singleton pregnancy, (3) ultrasonographic EFW ≤10th percentile between 36+0 and 37+6 In the control group, the sFlt-1/PlGF ratio will be concealed to weeks+days of gestation, (4) sFlt-1/PlGF ratio measured investigators and the standard Doppler-based approach will be between 36+0 and 37+6 weeks+days of gestation, (5) used for fetal monitoring [1]. Thus, fetuses with an EFW <3rd randomization between 36+0 and 37+6 weeks+days of gestation, percentile or ≤10th percentile accompanied by an abnormal and (6) gestational age confirmed by fetal crown-rump length feto-maternal Doppler (UA PI >95th percentile, MCA PI <5th measurement during the first trimester scan (from 11+0 to 13+6 percentile, CPR <5th percentile, UtA PI >95th percentile, or a weeks+days of gestation) or by in vitro fertilization dates. combination of these markers) [50-53] will be classified as FGR. The remaining cases will be classified as SGA. Exclusion Criteria In both groups, when a fetus is classified as FGR, immediate Exclusion criteria at the time of enrollment are as follows: (1) (within 24 hours) elective delivery at ≥37 weeks of gestation major fetal malformations or genetic disorders, (2) fetal death, will be recommended; when a fetus is classified as SGA, elective (3) absent or reversed end-diastolic flow in UA Doppler, (4) delivery will be delayed until 40 weeks of gestation. From nonreassuring CTG, (5) preeclampsia, (6) diminished fetal randomization to delivery, all SGA pregnancies in both groups movements, (7) biophysical profile score ≤6, (8) will receive weekly follow-ups consisting of fetal ultrasound oligohydramnios, and (9) refusal to give informed consent. (including fetal growth, amniotic fluid deepest vertical pocket, Intervention fetal movements, and feto-maternal Doppler), conventional CTG, and measurement of the sFlt-1/PlGF ratio (which will be First, gestational age (by fetal crown-rump length measurement concealed or revealed depending on the allocated group). at 11+0 to 13+6 weeks+days) [44] and EFW ≤10th percentile will be confirmed [45-49]. After giving their written informed In both groups, if at any time after enrollment any of the consent, trial participants will be randomized into 2 groups: following is present, immediate (within 24 hours) delivery will intervention and control. be recommended: UA with absent or reversed end-diastolic flow, nonreassuring CTG, PE, diminished fetal movements, In the intervention group, the sFlt-1/PlGF ratio will be revealed biophysical profile score ≤6, or oligohydramnios (largest vertical to investigators so they can act according to the results. When pocket <2 cm). The flow chart in Figure 1 illustrates the the sFlt-1/PlGF ratio is ≥38, the fetus will be classified as FGR. management of participants from consent through follow-up. https://www.researchprotocols.org/2022/10/e37452 JMIR Res Protoc 2022 | vol. 11 | iss. 10 | e37452 | p. 5 (page number not for citation purposes) XSL• FO RenderX JMIR RESEARCH PROTOCOLS Garcia-Manau et al Figure 1. Flow chart of study intervention and management. AEDF: absent end-diastolic flow; CPR: cerebroplacental ratio; CTG: cardiotocography; EFW: estimated fetal weight; MCA: middle cerebral artery; PI: pulsatility index; PlGF: placental growth factor; REDF: reversed end-diastolic flow; sFlt-1: soluble fms-like tyrosine kinase-1; UA: umbilical artery. According to recommendations of the National Institute for cesarean delivery will be as follows: prolonged labor, failed Health and Care Excellence (NICE) [54], labor will be induced induction of labor, nonreassuring CTG, placental abruption, in pregnancies with a Bishop score [55] ≤6 by promoting and PE with severe features requiring immediate delivery. Other cervical ripening with vaginal administration of dinoprostone less frequent indications may occur and will be classified as or misoprostol or with a cervical balloon, as per each site’s usual “other.” protocols (Table 1). Prolonged labor will be defined according to the NICE In pregnancies with a Bishop score >6, labor will be induced guidelines for intrapartum care of healthy women and babies by amniotomy, intravenous oxytocin infusion, or both in all [56]. According to these guidelines, a delay in the first stage of participating sites. Indications for elective cesarean delivery labor is suspected if cervical dilatation is <2 cm after 4 hours. will be as follows: at least 2 previous cesarean deliveries, UA After 2 hours, delay will be confirmed if progress is <1 cm, and with absent or reversed end-diastolic flow, nonreassuring CTG, oxytocin will be offered. Prolonged labor will be confirmed if abnormal fetal presentation (breech or transverse lie position), dilatation has increased <2 cm after 4 hours of oxytocin infusion. placental abruption, PE with severe features requiring immediate The maximum duration of cervical ripening treatment will vary delivery (pulmonary edema, serum creatinine >1.1 mg/dL, depending on the method, with 12 hours for the cervical balloon, oliguria [≤500 ml in 24 h or <20 ml/h], persistent hypertension 16 hours for misoprostol, and 24 hours for dinoprostone. Failed despite appropriate antihypertensive therapy, persistent cerebral induction of labor will be defined as not entering the active or visual disturbances, or eclampsia), and participants refusing phase of labor after cervical ripening along with 6 to 8 hours of induction of labor. Other less frequent indications may occur oxytocin infusion. and will be classified as “other.” Indications for intrapartum https://www.researchprotocols.org/2022/10/e37452 JMIR Res Protoc 2022 | vol. 11 | iss. 10 | e37452 | p. 6 (page number not for citation purposes) XSL• FO RenderX JMIR RESEARCH PROTOCOLS Garcia-Manau et al Table 1. Cervical ripening mechanisms used at each participating site. For labor induction, classification of fetuses as being small for gestational age or having fetal growth restriction will be based on the Doppler criteria, as in the control group [1]. Dinoprostone (Propess; Ferring Pharmaceuticals Ltd) was administered at a 10-mg dose with a vaginal delivery system. Misoprostol (Misofar; Exeltis Healthcare SL) was administered at a 25-µg dose with a vaginal tablet. Cervical balloons used a double-balloon catheter plus stylet (Cook Medical). Hospital Fetal growth restriction Small for gestational age Vall d’Hebron Dinoprostone Dinoprostone Torrejón Cervical balloon Dinoprostone Joan XXIII Misoprostol Misoprostol Alicante Dinoprostone Dinoprostone Arrixaca Dinoprostone Dinoprostone Parc Taulí Dinoprostone Dinoprostone Cabueñes Dinoprostone Dinoprostone Germans Trias Dinoprostone Dinoprostone Son Llàtzer Dinoprostone Dinoprostone Lozano Blesa Cervical balloon Dinoprostone Althaia Dinoprostone Dinoprostone A Coruña Dinoprostone Dinoprostone Elche Cervical balloon Dinoprostone Valme Cervical balloon Cervical balloon Hospital Terrassa Dinoprostone Misoprostol Mutua Terrassa Dinoprostone Misoprostol Getafe Cervical balloon Cervical balloon Puerta del Mar Cervical balloon Misoprostol Josep Trueta Misoprostol Misoprostol Candelaria Dinoprostone Dinoprostone In all settings, EFW will be calculated using the Hadlock Predictive Variables formula [49]. EFW percentiles will be calculated using the Predictive variables include maternal sFlt1 and PlGF plasma reference charts of each site’s protocol. Fetuses with an EFW levels (pg/ml), fetal EFW, results of a Doppler assessment (UA ≤10th percentile will be classified as small [45-48]. Doppler PI, MCA PI, CPR, and UtA PI percentiles), amniotic fluid assessments will be performed following the International vertical pocket, fetal movement and biophysical profile score, Society of Ultrasound in Obstetrics and Gynecology Practice and conventional CTG interpretation. PlGF and sFlt-1 levels Guidelines [58]. All participating sites will use the same will be measured using the automated Elecsys reference values for calculating UtA PI percentiles [51]. Doppler electrochemiluminescence immunoassay platform (Cobas percentiles for UA PI, MCA PI, and CPR will be calculated Analyzers; Roche Diagnostics). according to gestational age using the charts of each site’s Nonreassuring CTG before and during labor will be defined as protocol (Table 2). Gestational age will be determined by fetal sinusoidal fetal heart rate tracing or absent fetal heart rate crown-rump length measurement at 11+0 to 13+6 weeks+days variability accompanied by recurrent late decelerations, recurrent of gestation [44] or in vitro fertilization date. variable decelerations, or bradycardia [57]. https://www.researchprotocols.org/2022/10/e37452 JMIR Res Protoc 2022 | vol. 11 | iss. 10 | e37452 | p. 7 (page number not for citation purposes) XSL• FO RenderX JMIR RESEARCH PROTOCOLS Garcia-Manau et al Table 2. Reference charts at each participating site. Hospital Estimated fetal weight per- Umbilical artery pulsatility Middle cerebral artery pulsatil- Cerebroplacental ratio per- centile index percentile ity index percentile centile Vall d’Hebron Mikolajczyk RT et al [47] Ciobanu A et al [50] Ciobanu A et al [50] Ciobanu A et al [50] Torrejón Marsál K et al [48] Arduini D and Rizzo G [52] Baschat AA and Gembruch U Baschat AA and Gembruch U [53] [53] Joan XXIII Hadlock FP et al [49] Arduini D and Rizzo G [52] Baschat AA and Gembruch U Baschat AA and Gembruch U [53] [53] Alicante Mikolajczyk et al [47] Ciobanu A et al [50] Ciobanu A et al [50] Ciobanu A et al [50] Arrixaca Figueras F et al [45] Arduini D and Rizzo G [52] Baschat AA and Gembruch U Baschat AA and Gembruch U [53] [53] Parc Taulí Hadlock FP et al [49] Arduini D and Rizzo G [52] Baschat AA and Gembruch U Baschat AA and Gembruch U [53] [53] Cabueñes Hadlock FP et al [49] Arduini D and Rizzo G [52] Baschat AA and Gembruch U Baschat AA and Gembruch U [53] [53] Germans Trias Hadlock FP et al [49] Arduini D and Rizzo G [52] Baschat AA and Gembruch U Baschat AA and Gembruch U [53] [53] Son Llàtzer Figueras F et al [45] Arduini D and Rizzo G [52] Baschat AA and Gembruch U Baschat AA and Gembruch U [53] [53] Lozano Blesa Figueras F et al [45] Arduini D and Rizzo G [52] Baschat AA and Gembruch U Baschat AA and Gembruch U [53] [53] Althaia Figueras F et al [45] Arduini D and Rizzo G [52] Baschat AA and Gembruch U Baschat AA and Gembruch U [53] [53] A Coruña Figueras F et al [45] Arduini D and Rizzo G [52] Baschat AA and Gembruch U Baschat AA and Gembruch U [53] [53] Elche Papageorghiou AT et al [46] Ciobanu A et al [50] Ciobanu A et al [50] Ciobanu A et al [50] Valme Figueras F et al [45] Arduini D and Rizzo G [52] Baschat AA and Gembruch U Baschat AA and Gembruch U [53] [53] Hospital Terrassa Figueras F et al [45] Arduini D and Rizzo G [52] Baschat AA and Gembruch U Baschat AA and Gembruch U [53] [53] Mutua Terrassa Hadlock FP et al [49] Arduini D and Rizzo G [52] Baschat AA and Gembruch U Baschat AA and Gembruch U [53] [53] Getafe Figueras F et al [45] Arduini D and Rizzo G [52] Baschat AA and Gembruch U Baschat AA and Gembruch U [53] [53] Puerta del Mar Mikolajczyk et al [47] Ciobanu A et al [50] Ciobanu A et al [50] Ciobanu A et al [50] Josep Trueta Mikolajczyk et al [47] Ciobanu A et al [50] Ciobanu A et al [50] Ciobanu A et al [50] Candelaria Figueras F et al [45] Arduini D and Rizzo G [52] Baschat AA and Gembruch U Baschat AA and Gembruch U [53] [53] Amniotic fluid volume will be determined measuring the deepest pressure ≥110 mm Hg, or PE with any of the following signs vertical pocket and oligohydramnios will be considered when and symptoms: cerebral or visual symptoms, raised liver depth is <2 cm [59]. Depending on each site’s protocol, fetal enzymes, low platelet count, renal insufficiency, and pulmonary movement will be assessed subjectively or based on biophysical edema [61]. profile score, as described by Manning [60]. PE will be defined as new-onset high blood pressure (systolic blood pressure ≥140 Outcomes mm Hg or diastolic blood pressure ≥90 mm Hg), worsening of Primary Outcome previous high blood pressure in addition to new-onset The primary outcome is the prevalence of cesarean delivery due proteinuria (≥300 mg protein in a 24-hour urine collection, to nonreassuring fetal status or the prevalence of neonatal protein/creatinine ≥0.3, or a dipstick reading of 1+), worsening acidosis. Neonatal acidosis will be defined as a UA pH <7.15 of previous proteinuria, or according to at least one of the and a base excess greater than –12 mEq/L. following signs and symptoms: cerebral or visual symptoms, raised liver enzymes, low platelet count, renal insufficiency, Secondary Outcomes and pulmonary edema. PE with severe features will be defined Composite adverse perinatal outcome will be defined as the as either systolic blood pressure ≥160 mm Hg or diastolic blood presence of at least one of the following: fetal death, Apgar https://www.researchprotocols.org/2022/10/e37452 JMIR Res Protoc 2022 | vol. 11 | iss. 10 | e37452 | p. 8 (page number not for citation purposes) XSL• FO RenderX JMIR RESEARCH PROTOCOLS Garcia-Manau et al score <7 at 5 minutes, UA pH <7.05, admission to the NICU Mann-Whitney U test, as appropriate, will be used for or a transitional care unit within 48 hours, birthweight <2000 continuous variables. grams, maternal admission to the obstetric intensive care unit During the design stage of the trial, no financial support was within 48 hours (before or after delivery), and PE. available. Nevertheless, if this trial receives a specific grant Composite adverse neonatal outcomes will be defined as the from a funding agency, monitoring by the Academic Research presence of at least one of the following: respiratory distress Organization of the Vall d’Hebron Research Institute will be syndrome (respiratory rate >60 or <30 breaths/min, grunting contracted. on expiration, chest indrawing, central cyanosis, apnea, or the need for surfactant therapy in the neonatal period) [62], transient Sample Size tachypnea, required ventilatory support, grade III or IV A management protocol based on EFW and Doppler assessment intraventricular hemorrhage, neonatal sepsis, hypoglycemia, has shown a prevalence of adverse perinatal outcomes of 26%, necrotizing enterocolitis, neonatal jaundice (treated with meaning that there is a prevalence of 74% of pregnancies with phototherapy), neonatal seizures, pneumonia, meningitis, and no complications [25]. The estimated rate of pregnancies with neonatal death. no complications in the intervention group has been set at 74%, with a lower limit of 65.5% (a maximum achievable difference Other secondary outcomes will include the following: rates of of 8.5%). Based on these considerations and an estimated elective delivery before 38, 39, and 40 weeks of gestation; rates dropout rate of 3%, the sample size needed for a noninferiority of deliveries (elective and spontaneous) before 38, 39, and 40 design with a power of 80% and a significance level of 5% is weeks of gestation; rate of birthweight <2500 grams; rate of 1030 participants, that is, 515 in each group. Noninferiority will UA pH <7.10; rate of elective cesarean delivery; rate of cesarean be demonstrated if the lower limit of the 95% CI of the delivery due to failed labor induction; rate of emergency difference between incidences of pregnancies without neonatal operative vaginal delivery; and rate of placental-related acidosis is less than –8.5%. If the dropout rate is greater than complications, such as placental abruption, pregnancy 3%, the number of participants will be increased so as to achieve hypertension, severe PE, eclampsia, stroke, maternal death, and 1000 participants with complete data for the primary outcome. postpartum hemorrhage. Randomization, Masking, and Data Collection Statistical Analysis Participants will be randomly assigned to the intervention or Statistical analysis will be performed based on the control group in a 1:1 ratio using variable-size block intention-to-treat approach, considering all randomized women. randomization. The randomization sequence will be centralized A sensitivity analysis will be carried out to take into account and generated by the web-based system Sealed Envelope (Sealed the effect of withdrawal of consent and loss to follow-up. Envelope Ltd) and will be concealed to investigators. Owing Outcomes and covariates will be imputed by multiple imputation to the nature of the intervention, it will not be possible to conceal chain equations. Patients deemed ineligible after randomization the study group to the participants, investigators, or outcome (eg, due to identification of congenital defects or EFW >10th assessors. percentile) will be excluded in the per-protocol analysis. A RedCap (Research Electronic Data Capture; Vanderbilt Univariate descriptive analysis will be used for the study University) electronic database has been specifically designed variables. We will assess differences between the groups for for this study [64]. The electronic database has a randomization the primary and secondary outcomes, calculating differences module that will allow allocation of participants to the study in the incidence and relative risks with their respective 95% groups. Data will be entered prospectively during the study. CIs. Type I errors will be set at P<.05. The statistical software Access to this database will be restricted to the investigators packages R and R Studio (R Foundation) will be used for involved in each participating site. statistical analyses. An interim analysis will be performed by an independent statistician once 50% of the sample size has Ethics Approval been recruited. This analysis will ascertain the safety of the new The current version (version 3.0) of the study protocol was approach with the O’Brien-Fleming boundary [63]. As FGR approved by the Vall d’Hebron Ethics Committee pregnancies have a higher risk of stillbirth and other adverse (PR[AMI]527/2019) on February 18, 2020. Subsequent approval outcomes compared to SGA pregnancies, women with SGA by individual ethical committees has been granted. Written fetuses will probably be more willing to participate. Enrollment informed consent will be obtained from all participants before of a greater proportion of SGA pregnancies might hinder randomization. identification of differences between groups. For this reason, a subgroup analysis will be performed for FGR and SGA Results pregnancies according to the Doppler classification at enrollment. Categorical variables will be reported as frequencies, The first patient was recruited on September 28, 2020, and at normally distributed continuous variables will be reported as the time of submitting this manuscript, the study was in the means and standard deviations, and continuous variables that recruitment and data collection phase. The study results are do not follow a normal distribution will be reported as medians expected to be published in peer-reviewed journals and and interquartile ranges. The Fisher exact test or chi-square test, disseminated at international conferences in early 2023. No as appropriate, will be used to assess differences in categorical funding has been obtained for this trial. variables between groups. The Student t test (2-tailed) or https://www.researchprotocols.org/2022/10/e37452 JMIR Res Protoc 2022 | vol. 11 | iss. 10 | e37452 | p. 9 (page number not for citation purposes) XSL• FO RenderX JMIR RESEARCH PROTOCOLS Garcia-Manau et al will evaluate the effectiveness of both interventions in the Discussion conditions of real-life routine practice, which will allow Newborns under 39 weeks have poorer perinatal outcomes than extrapolating the results to other settings. On the other hand, full-term newborns [10]. After classification with EFW and the sample size will not allow assessment of the effect of the Doppler, more than 60% of small fetuses are delivered at 37 to management protocol on the incidence of rare adverse outcomes, 38 weeks of gestation [8]. However, classification with AF such as stillbirth, placental abruption, or eclampsia. All pregnant seems to have a lower false-positive rate [36]. In this trial, we women with fetuses having an EFW ≤10th percentile at 36+0 aim to assess whether the classification of small fetuses as FGR to 37+6 weeks+days of gestation will be invited to participate; or SGA based on AF is not inferior to the standard clinical however, since FGR pregnancies are at a higher risk of stillbirth approach (EFW and Doppler percentiles) for the identification and other adverse outcomes, women with FGR pregnancies of fetuses at a higher risk of adverse perinatal outcomes might be more reluctant to participate than women with SGA, (neonatal acidosis and cesarean section due to nonreassuring which could introduce a selection bias. CTG). This is the first trial that includes term pregnancies with The AF-based protocol may reduce the number of pregnancies an EFW below the 10th percentile and is designed to compare classified as FGR without worsening perinatal outcomes, perinatal outcomes with a management protocol based on the improve patients’ medical attention perception, reduce the rate sFlt-1/PlGF ratio and the standard management protocol, based of cesarean deliveries, and reduce the rate of placental on feto-maternal Doppler assessment. The main strength of this complications, such as PE, placental abruption, or eclampsia. study is the comparison of 2 randomized groups and the large Moreover, the rate of early-term neonates may be reduced, size of the study population. A pragmatic and multicenter design improving neonatal outcomes and long-term morbidity. Acknowledgments Roche Diagnostics provided the reagents used for the placental growth factor and soluble fms-like tyrosine kinase-1 measurements. 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[accessed 2022-09-30] Abbreviations AF: angiogenic factors CPR: cerebroplacental ratio CTG: cardiotocography EFW: estimated fetal weight FGR: fetal growth restriction MCA: middle cerebral artery NICE: National Institute for Health and Care Excellence NICU: neonatal intensive care unit PE: preeclampsia PI: pulsatility index PlGF: placental growth factor sFlt-1: soluble fms-like tyrosine kinase-1 SGA: small for gestational age SPIRIT: Standard Protocol Items: Recommendations for Interventional Trials UA: umbilical artery UtA: uterine artery https://www.researchprotocols.org/2022/10/e37452 JMIR Res Protoc 2022 | vol. 11 | iss. 10 | e37452 | p. 13 (page number not for citation purposes) XSL• FO RenderX JMIR RESEARCH PROTOCOLS Garcia-Manau et al Edited by T Leung; submitted 22.02.22; peer-reviewed by S Ouyang; comments to author 01.08.22; revised version received 20.09.22; accepted 20.09.22; published 11.10.22 Please cite as: Garcia-Manau P, Mendoza M, Bonacina E, Martin-Alonso R, Martin L, Palacios A, Sanchez ML, Lesmes C, Hurtado I, Perez E, Tubau A, Ibañez P, Alcoz M, Valiño N, Moreno E, Borrero C, Garcia E, Lopez-Quesada E, Diaz S, Broullon JR, Teixidor M, Chulilla C, Gil MM, Lopez M, Candela-Hidalgo A, Salinas-Amoros A, Moreno A, Morra F, Vaquerizo O, Soriano B, Fabre M, Gomez-Valencia E, Cuiña A, Alayon N, Sainz JA, Vives A, Esteve E, Ocaña V, López MÁ, Maroto A, Carreras E 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 JMIR Res Protoc 2022;11(10):e37452 URL: https://www.researchprotocols.org/2022/10/e37452 doi: 10.2196/37452 PMID: ©Pablo Garcia-Manau, Manel Mendoza, Erika Bonacina, Raquel Martin-Alonso, Lourdes Martin, Ana Palacios, Maria Luisa Sanchez, Cristina Lesmes, Ivan Hurtado, Esther Perez, Albert Tubau, Patricia Ibañez, Marina Alcoz, Nuria Valiño, Elena Moreno, Carlota Borrero, Esperanza Garcia, Eva Lopez-Quesada, Sonia Diaz, Jose Roman Broullon, Mireia Teixidor, Carolina Chulilla, Maria M Gil, Monica Lopez, Amparo Candela-Hidalgo, Andrea Salinas-Amoros, Anna Moreno, Francesca Morra, Oscar Vaquerizo, Beatriz Soriano, Marta Fabre, Elena Gomez-Valencia, Ana Cuiña, Nicolas Alayon, Jose Antonio Sainz, Angels Vives, Esther Esteve, Vanesa Ocaña, Miguel Ángel López, Anna Maroto, Elena Carreras. 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