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

Abstract

Background Routine 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. Methods International 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. Discussion The CEPRA trial will identify whether the CPR is a good indicator for delivery in women with perceived reduced fetal movements. Trial registration Dutch trial registry (NTR), trial NL7557. Registered 25 February 2019.

Fetal Growth Restriction: Mechanisms, Epidemiology, and Management

“…76 Currently the CEPRA trial investigates the role of Doppler measurements for timing of delivery in case of RFM at term. 69…”

“…The cerebroplacental ratio (CPR) (the ratio of MCA PI and UmbA PI) is a measure for brainsparing and it improves the sensitivity of Doppler monitoring because it already increases when its two components are still within the normal range 2,68 . It is not known how to use CPR in the monitoring management strategy for suspected FGR, for this reason multiple trials are underway such as DRIGITAT (NL6475, NTR 6663), CEPRA (NL 7557), RATIO37, TRUFFLE2 (IRAS Project ID: 266400) 69,70 …”

Cerebral Blood Flow Monitoring in High-Risk Fetal and Neonatal Populations

“…These technologies will not replace the inexpensive and readily-available method of Doppler ultrasound for CBF monitoring anytime soon, thus studies to maximize our knowledge and utilization of this tool are also warranted. The CEPRA study (Dutch Trial Registry NTR trial NL7557) is an example of how the fetal Doppler CBF monitoring field is moving forward, the goal of which is to determine the utility of CPR as an indicator for immediate delivery in pregnant people reporting loss of fetal movement ( 167 ). These types of multicenter studies are essential to have an impact on clinical practice of fetal monitoring technologies that have already been studied for many years.…”

Fetal movement trials: Where is the evidence in settings with a high burden of stillbirths?

“…In the UK, the AFFIRM trial investigated the effects of an FM awareness package coupled with a standardised management protocol 5 . The ongoing CEPRA study in the Netherlands, UK and Australia aims to evaluate Cerebro Placental Ratio as an indicator for delivery in women with reduced FM 6 . None of the completed trials, however, found significant reductions in stillbirths.…”