The CErebro Placental RAtio as indicator for delivery following perception of reduced fetal movements, protocol for an international cluster randomised clinical trial; the CEPRA study

Stefanie E Damhuis,Sanne J Gordijn,Henk Groen,Alexander E P Heazell,Wessel Ganzevoort,Ruben G Duijnhoven,Sailesh Kumar,Asma Khalil

doi:10.1186/s12884-021-03760-2

Abstract

BackgroundRoutine assessment in (near) term pregnancy is often inaccurate for the identification of fetuses who are mild to moderately compromised due to placental insufficiency and are at risk of adverse outcomes, especially when fetal size is seemingly within normal range for gestational age. Although biometric measurements and cardiotocography are frequently used, it is known that these techniques have low sensitivity and specificity. In clinical practice this diagnostic uncertainty results in considerable ‘over treatment’ of women with healthy fetuses whilst truly compromised fetuses remain unidentified. The CPR is the ratio of the umbilical artery pulsatility index over the middle cerebral artery pulsatility index. A low CPR reflects fetal redistribution and is thought to be indicative of placental insufficiency independent of actual fetal size, and a marker of adverse outcomes. Its utility as an indicator for delivery in women with reduced fetal movements (RFM) is unknown. The aim of this study is to assess whether expedited delivery of women with RFM identified as high risk on the basis of a low CPR improves neonatal outcomes. Secondary aims include childhood outcomes, maternal obstetric outcomes, and the predictive value of biomarkers for adverse outcomes.MethodsInternational multicentre cluster randomised trial of women with singleton pregnancies with RFM at term, randomised to either an open or concealed arm. Only women with an estimated fetal weight ≥ 10th centile, a fetus in cephalic presentation and normal cardiotocograph are eligible and after informed consent the CPR will be measured. Expedited delivery is recommended in women with a low CPR in the open arm. Women in the concealed arm will not have their CPR results revealed and will receive routine clinical care. The intended sample size based on the primary outcome is 2160 patients. The primary outcome is a composite of: stillbirth, neonatal mortality, Apgar score < 7 at 5 min, cord pH < 7.10, emergency delivery for fetal distress, and severe neonatal morbidity.DiscussionThe CEPRA trial will identify whether the CPR is a good indicator for delivery in women with perceived reduced fetal movements.Trial registrationDutch trial registry (NTR), trial NL7557. Registered 25 February 2019.

Highlights

Routine assessment in term pregnancy is often inaccurate for the identification of fetuses who are mild to moderately compromised due to placental insufficiency and are at risk of adverse outcomes, especially when fetal size is seemingly within normal range for gestational age
The CEPRA trial will identify whether the cerebroplacental ratio (CPR) is a good indicator for delivery in women with perceived reduced fetal movements
If the onset of placental insufficiency occurs in late gestation, fetal size is more likely to be within the normal range and the chronic placental dysfunction remains undetected

Summary

Methods

Study objective To assess whether expedited delivery (induction of delivery within 16 h) in pregnancies at term complicated with RFM and an abnormal CPR (< 1.1) improves neonatal outcome as compared to clinical management where the CPR remains concealed. Study design We will conduct an international cluster randomised controlled clinical trial with randomisation at hospital level to either an open (CPR revealed) or concealed arm, performed in the Netherlands, UK and Australia. The budget impact analysis of management based on CPR in women with RFM will be performed according to the ISPOR guidelines from a societal perspective as well from the health insurance and/or Dutch healthcare budgeting framework perspective [32]. Randomisation at cluster level was postulated to lead to a better implementation of the intervention in participating sites This cluster RCT will determine whether the CPR is an effective marker to guide management in pregnancies at term complicated with RFM.

Discussion

Background

Findings