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This is an open-label prospective single-center randomized controlled trial to evaluate the effect of intranasal breast milk in hypoxic-ischemic encephalopathic neonates receiving therapeutic hypothermia on long term neurodevelopmental outcome compared to standard care.
Perinatal asphyxia and the resulting hypoxic-ischemic encephalopathy (HIE) are the leading cause of neonatal mortality and long-term neurodevelopmental disabilities. Based on our current knowledge, therapeutic hypothermia is the only therapy that has been proven to reduce central nervous system damage in HIE neonates. Improving neurodevelopmental outcomes of newborns with HIE has been an intense area of research over the past decade.
Breast milk is a complex biological substance that contains a variety of bioactive components including neurotrophic growth factors, cytokines, immunoglobulins, and multipotent stem cells. Studies have shown that exclusive breastfeeding in the early stages of development has a positive impact on cognitive outcomes. Animal studies support that mesenchymal stem cells and neurotrophic substances found in breast milk, when administered intranasally enter the central nervous system and reduce the extent of neurological damage. In preterm infants, it has been shown that intranasally administered breast milk is safe and well-tolerated.
In this open-label prospective randomized controlled single-center interventional study, the objective is to administer fresh, own-mother's breast milk intranasally to neonates with hypoxic-ischemic encephalopathy receiving therapeutic hypothermia, starting from the first day of life and continuing for 28 days.
The primary objective is to compare neurodevelopmental outcomes between the control group and the intervention group receiving intranasal breast milk treatment. The secondary objective is to compare the progression of enteral feeding and the duration of exclusive breastfeeding between the intervention and the control group.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Control | No Intervention | Standard care for moderate or severe hypoxic-ischemic encephalopathy with hypothermia. | |
| Intranasal breast milk | Experimental | Fresh own mother's breast milk expressed within 4 hours, will be administered 2 times daily, 0.4 ml in each nostril for 28 days. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Intranasal breast milk | Biological | Own-mother's fresh breast milk (within 4 hours of having been expressed), is administered intranasally to neonates with hypoxic-ischemic encephalopathy receiving therapeutic hypothermia, starting from the first day of life and continuing for 28 days. Dose: 2 times daily, 0.4 ml in each nostril. |
| Measure | Description | Time Frame |
|---|---|---|
| Neurodevelopmental outcome | The primary outcome will be the 2 year neurodevelopmental outcome comparing standard care and intranasal breast milk therapy groups. The Bayley Scales of Infant Development, Third Edition (Bayley-III) score will be used to assess neurodevelopmental outcome, favorable outcome is defined as having composite scores for cognitive, language and motor scales >85, while adverse outcome is defined as composite scores <80 or death. | 2 years |
| Measure | Description | Time Frame |
|---|---|---|
| Time to reach full enteral feeding | Time to reach full enteral feeding will be recorded and analyzed as a secondary outcome. | 1 month |
| Length of exclusive breast feeding | Lengths of exclusive breast feeding will be recorded and analyzed as a secondary outcome. |
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Inclusion Criteria:
Moderate or severe hypoxic- ischemic encephalopathy, receiving therapeutic hypothermia
≥ 35. gestational week < 48 hours of life
Hypothermia treatment for 72 hours
Parental consent form
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Unoke Meder, MD, PhD | Contact | +36303987970 | mederunoke@gmail.com | |
| Agnes Jermendy, MD, PhD | Contact | +36204600798 | jermendy@gmail.com |
| Name | Affiliation | Role |
|---|---|---|
| Unoke Meder, MD, PhD | Department of Neonatology, Pediatric Center, Semmelweis University, Budapest, Hungary | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Department of Neonatology, Pediatric Center, Semmelweis University, Budapest, Hungary | Recruiting | Budapest | 1083 | Hungary |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 38336090 | Background | Chen Y, Zhang C, Huang Y, Ma Y, Song Q, Chen H, Jiang G, Gao X. Intranasal drug delivery: The interaction between nanoparticles and the nose-to-brain pathway. Adv Drug Deliv Rev. 2024 Apr;207:115196. doi: 10.1016/j.addr.2024.115196. Epub 2024 Feb 7. | |
| 35568047 | Background | Baak LM, Wagenaar N, van der Aa NE, Groenendaal F, Dudink J, Tataranno ML, Mahamuud U, Verhage CH, Eijsermans RMJC, Smit LS, Jellema RK, de Haan TR, Ter Horst HJ, de Boode WP, Steggerda SJ, Prins HJ, de Haar CG, de Vries LS, van Bel F, Heijnen CJ, Nijboer CH, Benders MJNL. Feasibility and safety of intranasally administered mesenchymal stromal cells after perinatal arterial ischaemic stroke in the Netherlands (PASSIoN): a first-in-human, open-label intervention study. Lancet Neurol. 2022 Jun;21(6):528-536. doi: 10.1016/S1474-4422(22)00117-X. |
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On special request pending data transfer agreement approval by Semmelweis University.
20.12.2024.-01.01.2030.
On special request pending data transfer agreement approval by Semmelweis University. Sharing upon reasonable request.
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| ID | Term |
|---|---|
| D020925 | Hypoxia-Ischemia, Brain |
| ID | Term |
|---|---|
| D002545 | Brain Ischemia |
| D002561 | Cerebrovascular Disorders |
| D001927 | Brain Diseases |
| D002493 | Central Nervous System Diseases |
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|
| 2 years |
| 38688998 | Background | Hoban R, Gallipoli A, Signorile M, Mander P, Gauthier-Fisher A, Librach C, Wilson D, Unger S. Feasibility of intranasal human milk as stem cell therapy in preterm infants with intraventricular hemorrhage. J Perinatol. 2024 Nov;44(11):1652-1657. doi: 10.1038/s41372-024-01982-8. Epub 2024 Apr 30. |
| 30386923 | Background | Keller T, Korber F, Oberthuer A, Schafmeyer L, Mehler K, Kuhr K, Kribs A. Intranasal breast milk for premature infants with severe intraventricular hemorrhage-an observation. Eur J Pediatr. 2019 Feb;178(2):199-206. doi: 10.1007/s00431-018-3279-7. Epub 2018 Nov 1. |
| D009422 | Nervous System Diseases |
| D002534 | Hypoxia, Brain |
| D014652 | Vascular Diseases |
| D002318 | Cardiovascular Diseases |
| D000860 | Hypoxia |
| D012818 | Signs and Symptoms, Respiratory |
| D012816 | Signs and Symptoms |
| D013568 | Pathological Conditions, Signs and Symptoms |