Intranasal Fresh Mother's Own Milk to Prevent Intraventricular Hemorrhage in Extremely Preterm Infants

Intranasal Fresh Mother's Own Milk (iF-MOM) for Prevention of Intraventricular Hemorrhage in Extremely Preterm Infants ≤29 Weeks' Gestational Age: A Prospective, Nonrandomized Interventional Study With Propensity Score-Weighted Historical Controls

Babies born very prematurely are at risk of intraventricular hemorrhage (IVH), which is bleeding in or around the fluid-filled spaces of the brain. Most IVH occurs during the first week after birth. Human colostrum and early breast milk contain growth factors, neurotrophic factors, immune-modulating substances, antioxidants, and other biologically active components that may have neuroprotective effects.

This study will evaluate whether giving very small amounts of a baby's own mother's fresh breast milk as nasal drops during the first 7 days of life may help prevent IVH in infants born at 29 weeks' gestation or earlier.

Approximately 67 eligible infants will be enrolled prospectively at Women's Hospital and St. Boniface Hospital in Winnipeg, Manitoba, Canada. At each scheduled study care session, fresh mother's own milk will be administered intranasally at 0.2 mL per nostril (0.4 mL total) before routine nursing care and, if tolerated and the infant remains clinically stable, repeated after care. Thus, a completed care session provides up to 0.8 mL. Study administration will be coordinated with 2-4 routine care sessions per day for 7 consecutive days, corresponding to a planned total daily volume of 1.6-3.2 mL.

The main study outcome is whether IVH of any grade is present on the routine cranial ultrasound performed at 4 to 7 days of life. Other outcomes include severe IVH, progression of IVH, post-hemorrhagic ventricular complications, mortality before hospital discharge, and the safety and tolerability of intranasal mother's own milk.

Outcomes in the prospectively treated infants will be compared with those of eligible infants previously cared for at the same neonatal intensive care units between 2020 and 2025. Statistical methods using propensity score weighting will be used to account for measured differences between the prospectively treated infants and the historical comparison group.

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.

Inclusion Criteria:

1. Gestational age ≤29+0 weeks based on the best obstetric estimate, with first-trimester ultrasound preferred.
2. Inborn at Women's Hospital or St. Boniface Hospital, Winnipeg, Manitoba, Canada.
3. Written informed consent obtained from a parent or legal guardian; antenatal consent may be obtained when preterm delivery is anticipated.
4. Mother/birthing parent intends and is able to provide fresh own milk for study dosing; low initial milk volume is acceptable because of the small intranasal dosing requirements.
5. Enrollment within 72 hours of life.

Exclusion Criteria:

1. Major congenital brain malformation, including holoprosencephaly, lissencephaly, schizencephaly, severe primary hydrocephalus, large arachnoid cyst, or other space-occupying lesion.
2. Airway or nasal anomaly precluding intranasal administration, including choanal atresia/stenosis, severe cleft palate/lip with nasal involvement, or Pierre Robin sequence with severe obstruction.
3. Trisomy 13, Trisomy 18, or another severe chromosomal/genetic disorder.
4. Acute surgical condition requiring immediate intervention, such as esophageal atresia with tracheoesophageal fistula.
5. Life-limiting condition, including comfort-care designation, anticipated survival <72 hours, known lethal diagnosis such as bilateral renal agenesis or anencephaly, or severe birth asphyxia with anticipated poor neurologic outcome.
6. Maternal contraindication to lactation, including HIV, or inability/unwillingness to provide fresh mother's own milk.
7. Evidence of Grade III-IV intraventricular hemorrhage on cranial ultrasound before enrollment.
8. Absence of fresh own-mother/birthing-parent milk for study dosing, including circumstances in which only donor or surrogate-provided milk is available.