Intranasal Fresh Mother's Own Milk to Prevent Intraventricular Hemorrhage in Extremely Preterm Infants (iF-MOM-IVH)

Intraventricular hemorrhage (IVH) remains an important complication of extreme prematurity and occurs predominantly during the first postnatal week. The immature germinal matrix vasculature, impaired cerebral autoregulation, hemodynamic instability, inflammation, oxidative stress, and other factors contribute to vulnerability to hemorrhage in extremely preterm infants.

Fresh colostrum and early mother's own milk contain multiple biologically active constituents with potential neuroprotective effects, including growth factors, neurotrophins, anti-inflammatory and immune-modulating mediators, antioxidants, and other bioactive components. Intranasal administration is being evaluated as a non-invasive route that may permit exposure of the central nervous system to milk-derived bioactive factors through proposed olfactory, trigeminal, perineural, and perivascular pathways.

This is a prospective, nonrandomized interventional study conducted at Women's Hospital and St. Boniface Hospital in Winnipeg, Manitoba, Canada. Eligible inborn infants at 29+0 weeks' gestation or less will be prospectively enrolled within 72 hours of birth. Enrolled infants will receive intranasal fresh mother's own milk during the first 7 days of life.

Fresh milk from the infant's own mother or birthing parent will be used. Milk used for study dosing will not be refrigerated or frozen before intranasal administration and will be used within 3 hours of expression. Each study dose consists of 0.2 mL administered into each nostril, for a total of 0.4 mL per dose. Doses will be administered 2 to 4 times daily for 7 consecutive days, coordinated with routine nursing care when possible. Clinical feeding and oral immune therapy needs will take priority over study dosing.

Infants will remain on continuous cardiorespiratory monitoring and pulse oximetry. Safety assessments will be performed during dosing and for at least 60 minutes after each administration. Study dosing may be delayed, withheld, or stopped if prespecified clinical instability or safety concerns occur.

The primary outcome is the presence of any IVH, Papile Grades I-IV, on cranial ultrasound performed at 4 to 7 days of life. Secondary outcomes include severe IVH, progression of IVH on subsequent imaging, post-hemorrhagic ventricular complications requiring intervention, all-cause mortality through hospital discharge, and safety and tolerability outcomes related to intranasal administration.

The study will enroll approximately 67 prospectively treated infants. Their outcomes will be compared with those of up to 188 historical controls admitted to the same two neonatal intensive care units between January 1, 2020 and December 31, 2025. Historical controls will meet the prespecified eligibility criteria and must have a documented cranial ultrasound at 4 to 7 days of life.

Because participants are not randomized to a concurrent control group, propensity scores will be estimated using prespecified maternal and neonatal characteristics. Stabilized inverse probability of treatment weighting and weighted regression methods will be used to reduce measured baseline imbalance between the prospectively treated infants and historical controls. The primary cranial ultrasound outcome will be assessed by a reviewer blinded to intervention versus historical-control status.

An optional mechanistic sub-study will permit storage and analysis of small leftover aliquots of study milk from Day 1 and Day 7, when sufficient milk remains after clinical and study dosing requirements are met. These samples will be used for approved analyses of selected naturally occurring milk components, including growth factors and neurotrophins.