Mechanisms Affecting the Gut of Preterm Infants Receiving Blood Transfusion With Different Enteral Feed Interventions

MAGPIE-2 is a mechanistic observational study nested within the WHEAT International randomised controlled trial, which compares two standard neonatal care practices: withholding versus continuing enteral feeds during red blood cell transfusion in very preterm infants. While WHEAT evaluates clinical outcomes such as necrotising enterocolitis (NEC), MAGPIE-2 is designed to explore the physiological mechanisms that may underlie the development of NEC in this context.

NEC is a leading cause of morbidity and mortality in extremely preterm infants, with onset often temporally associated with blood transfusion. The pathophysiology is thought to involve gut ischaemia, inflammation, and impaired perfusion, but the precise mechanisms remain unclear. MAGPIE-2 addresses this gap by applying non-invasive monitoring techniques to assess gut and brain oxygenation and perfusion in infants undergoing transfusion.

The study will recruit 270 infants (135 per arm) already enrolled in the WHEAT trial. These infants will undergo weekly and peri-transfusion assessments using near-infrared spectroscopy (NIRS) and Doppler ultrasound. NIRS will measure cerebral and splanchnic (gut) tissue oxygenation, allowing calculation of the Splanchnic-Cerebral Oxygenation Ratio (SCOR), a validated marker of gut perfusion. Doppler ultrasound will assess blood flow in the superior mesenteric artery (SMA), which supplies the gut regions most vulnerable to NEC.

Measurements will be taken:

Weekly (2-hour NIRS and SMA Doppler) until 34 weeks corrected gestational age or discharge Peri-transfusion: continuous NIRS from 4 hours before to 4 hours after transfusion (12-hour window), and 2-hour recordings at approximately 24 and 48 hours post-transfusion The primary outcome is the relative change in SCOR post-transfusion between the two feeding strategies. Secondary outcomes include changes in cerebral and splanchnic oxygenation, SMA peak systolic and diastolic velocities, and the relationship between pre-transfusion haemoglobin levels and perfusion metrics. The study also includes an assessment of inter-operator variability in Doppler measurements and a mediation analysis to explore causal pathways.

MAGPIE-2 will use mixed-effects regression models to account for within-subject and within-centre variability, and propensity score weighting to adjust for selection bias. The study is powered to detect a 20% absolute difference in SCOR, which is considered clinically significant for identifying gut ischaemia.

By integrating physiological data with clinical trial design, MAGPIE-2 aims to provide mechanistic evidence to support safer transfusion and feeding practices in neonatal care. The findings may inform future guidelines and reduce the incidence of NEC in this high-risk population.

• Change in Cerebral Oxygenation (crSO2) Post-Transfusion [Time frame: Continuous from 4 hours pre-transfusion to 4 hours post-transfusion (12-hour window) for each transfusion received with WHEAT Trial intervention; plus additional weekly 2-hour recordings until 34 weeks corrected age or neonatal discharge.]
• Change in Splanchnic Oxygenation (srSO2) Post-Transfusion [Time frame: Continuous from 4 hours pre-transfusion to 4 hours post-transfusion (12-hour window) for each transfusion received with WHEAT Trial intervention; plus additional weekly 2-hour recordings until 34 weeks corrected age or neonatal discharge.]
• Change in SMA Peak Systolic Velocity Post-Transfusion [Time frame: Weekly Doppler ultrasound assessments until 34 weeks corrected age or neonatal discharge.]
• Change in SMA Diastolic Velocity Post-Transfusion [Time frame: Weekly Doppler ultrasound assessments until 34 weeks corrected age or neonatal discharge.]
• Relationship Between Pre-Transfusion Haemoglobin and SCOR, crSO2, srSO2 [Time frame: Continuous from 4 hours pre-transfusion to 4 hours post-transfusion (12-hour window) for each transfusion received with WHEAT Trial intervention; plus additional NIRS weekly 2-hour recordings until 34 weeks corrected age or neonatal discharge.]
• Relationship Between Haemoglobin and SMA Doppler Parameters [Time frame: Weekly Doppler ultrasound assessments until 34 weeks corrected age or neonatal discharge.]
• Inter-Operator Variability in SMA Doppler Measurements [Time frame: One-time assessment during weekly Doppler ultrasound in a subset of 35 infants across 7 centres.]