Third Trimester Screening of Fetal Growth Restriction (RELAIS)

Single Scan Screening of Fetal Growth Restriction Versus Longitudinal Scan Screening in the Third Trimester: a Multicenter Randomized Protocol

The aim of this trial is to assess the efficacy and efficiency of the national and the research sonographic screening protocols for fetal growth disorders. In particular, in Italy at the moment we have two different national screening protocols: the traditional one providing an early third trimester scan at 28-32 weeks'gestation, and a more recent one, according to the new LEA (livelli essenziali di assistenza), providing a growth scan during the third trimester only if there is a clinical indication. Both these national protocols will be compared to a research protocol providing a late third trimester scan between 35 and 37 weeks'gestation in terms of sensibility and specificity.

3. PURPOSES AND OBJECTIVES OF THE CLINICAL TRIAL The aim of this trial is to assess the efficacy and efficiency of the national and the research sonographic screening protocols for fetal growth disorders. In particular, in Italy at the moment we have two different national screening protocols: the traditional one providing an early third trimester scan at 28-32 weeks'gestation, and a more recent one, according to the new LEA (livelli essenziali di assistenza), providing a growth scan during the third trimester only if there is a clinical indication. Both these national protocols will be compared to a research protocol providing a late third trimester scan between 35 and 37 weeks'gestation in terms of sensibility and specificity. 4. EXPERIMENTAL DESIGN 4.1 STUDY ENDPOINTS This study is designed to generate level 1 evidence of diagnostic efficacy. MAIN OUTCOME: The main outcome of the two protocols in screening true late preterm and term SGA fetuses is measured based Italian newborn weight charts centiles <the 10th according to gestational age and gender at delivery. SECONDARY OUTCOME The screen positive and screen negative results for the two protocols Early-TT, and Late-TT are based only on AC biometry and/or fetal weight <10th centile or crossing 50th centiles at scheduled exams, for the protocol TT-Indication are based on results at first medical indication. Mode of delivery Caesarean section rate according to Robson classes for singleton Composite mild adverse neonatal outcome (Apgar score at 5 minutes <7, pH < 7.10, or BD >8mmol/L, admission at NICU) Composite severe adverse perinatal (stillbirth or term live birth associated with neonatal death, hypoxic ischaemic encephalopathy, use of inotropes, need for mechanical ventilation, or severe metabolic acidosis (defined as a cord blood pH <7•0 and base deficit >12 mmol/L) TERTIARY OUTCOME Number of ultrasound scans performed in outpatient clinics by medical indication (SSR-prescription) beyond Early-TT and late-TT scheduled exams, and number of ultrasound scans performed on indication in outpatient clinics minus the first one indicated. Number of ultrasound scans by patient choice Econometrics of the two protocols, and of the estimated sanitary costs of outcomes 4.2 EXPERIMENTAL PLAN Women who agree to participate are randomized to the local regional Protocol vs Late-TT protocols. Basing on the different Regions'protocols the third trimester screening is performed either in the early third trimester at 28-32 weeks of gestation (Early Third Trimester screening - Early-TT) or only on clinical indication (Third Trimester on Indication - TT-indication). For this reason, this trial will be in fact split into two independents parallel randomisation. In practical terms this mean that women who agree to take part into the trial and sign an informed consent, will be randomized to the Early third trimester Protocol (Early-TT), vs Late Third Trimester Protocol (Late-TT)(Trial n°1) or to Third Trimester U/S on indication (TT-Indication) vs Late Third Trimester Protocol (Late-TT)(Trial n°2). 5. STUDY POPULATION 5.1 SAMPLE SIZE Sample size was calculated based on results by Roma et al2 considering a sensitivity of Early-TT in detecting SGA at birth (birth weight below 10th centile) of 22.5% compared to 38.8% of Late-TT, and Sovio et al considering a sensitivity of 20% compared to 57%, a confidence level of 95% (1-alpha) and an 80% power (1-beta), and a one to one ratio between the TT-Indication and the Late-TT arms. According to Fleiss14 each arm should be 138, which implies 270 for two arms of the Early-TT vs Late-TT, and 101 for the two arms TT-Indication vs Late-TT considering the 10% of the SGA population. The sample size needed considering both AGA and SGA, will then be 270 x10=2700 and 101x10=1010 pregnant women for the two randomizations respectively. Considering 10% of drop-out and incomplete data the final sample size should be increased of such percentage in each branch of the study. It has to be acknowledged that in the Late-TT arm there will be an additional split of the women after the randomization allocation based on the uterine artery Doppler velocimetry result. However, when calculating the sample size we did not take into account this secondary partition because we aim to consider the overall performance of Late-TT in identifying late preterm and term SGA as a primary outcome. 5.2 PATIENT SELECTION 5.2.1 INCLUSION CRITERIA Eligible cases are nulliparous pregnant women, with first trimester ultrasound assessment of gestational age, who conceived singleton fetuses. If the crown-rump-length (CRL) differs of more than ± 3-5 days from the last menstrual period, gestational age is calculated on the CRL. 5.2.2 EXCLUSION CRITERIA major medical disease high risk for preeclampsia on history or detected in those centres that perform pre-eclampsia screening at first trimester women older than 40 years on ASA low dose prophylaxis known immune disorders or clinical thrombophilic conditions; twin pregnancies; ovodonations suspected fetal anomalies at any gestational age Papp-A at Combined-Test<0.2 5.3 WITHDRAWAL PROCEDURES If a patient, during the study protocol, wanted to withdrawal, this will not modify the subsequent monitoring of her pregnancy following local protocols. 6. SUBJECT TREATMENT • RANDOMIZATION : Patients who agree to participate and sign an informed consent, Women who agree to participate are randomized to the local regional Protocol vs Late-TT protocols. There will be two different arms in each clinic: The Early third trimester Protocol (Early-TT) versus the Late Third Trimester Protocol

Third Trimester U/S on indication (TT-Indication) vs Late Third Trimester Protocol (Late-TT)(Trial n°2).

neonatal ossigenation and ph Composite severe adverse perinatal (stillbirth or term live birth associated with neonatal death, hypoxic ischaemic encephalopathy, use of inotropes, need for mechanical ventilation, or severe metabolic acidosis (defined as a cord blood pH <7•0 and base deficit >12 mmol/L)

Inclusion Criteria: Eligible cases are nulliparous pregnant women, with first trimester ultrasound assessment of gestational age, who conceived singleton fetuses. If the crown-rump-length (CRL) differs of more than ± 3-5 days from the last menstrual period, gestational age is calculated on the CRL. Exclusion Criteria: major medical disease high risk for preeclampsia on history or detected in those centres that perform pre-eclampsia screening at first trimester women older than 40 years on ASA low dose prophylaxis known immune disorders or clinical thrombophilic conditions; twin pregnancies; ovodonations suspected fetal anomalies at any gestational age Papp-A at Combined-Test<0.2