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| Name | Class |
|---|---|
| University of Oslo | OTHER |
| Umeå University | OTHER |
| University of Geneva, Switzerland | OTHER |
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The primary objective of this double-blind randomized study is to assess the effects of an early, enhanced supply of the essential fatty acids (FAs) arachidonic acid (ARA) and docosahexaenoic acid (DHA) on brain maturation, clinical outcomes and quality of growth in immature infants (gestational age <29 weeks) as compared to standard nutrient supply.
This is a double-blind randomized study. 172 preterm infants with gestational age < 29 weeks will be enrolled. The intervention group will receive enteral supplementation with essential fatty acids, arachidonic acid (ARA) and docosahexaenoic acid (DHA). The control group will receive standard supplementation with medium-chain triglycerides (MCT-oil). The main hypothesis is that early, enhanced supply of ARA and DHA will improve brain growth and maturation, as compared to standard nutrient supply. Secondary hypotheses are that early, enhanced supply of ARA and DHA will improve quality of growth and cognitive development as well as reduce the frequency of inflammation-related neonatal comorbidities and long-term cardiovascular disease risk. Primary endpoint will be assessed by magnetic resonance imaging (MRI) of the brain at term equivalent age.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Formulaid | Experimental | The intervention group will receive enteral supplementation with Formulaid containing ARA and DHA at a ratio of 2:1, from birth until 36 weeks PMA |
|
| MCT-oil | Active Comparator | The control group will receive enteral supplementation with MCT oil containing coconut and/or palm kern oil, from birth until 36 weeks PMA |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Formulaid | Dietary Supplement | Supplementation with ARA and DHA |
| |
| Measure | Description | Time Frame |
|---|---|---|
| Brain maturation assessed by magnetic resonance imaging (MRI) | MRI with spectroscopy (MRS) and diffusion tensor imaging (DTI) will be used to examine myelinisation and quantification of anatomical structures as well as neuronal integrity and inflammation | 40 weeks postmenstrual age (PMA) |
| Measure | Description | Time Frame |
|---|---|---|
| Weight gain | Weight measurements, including weight nadir. | Weight will be recorded until 36 weeks PMA and at 3, 6, 12 and 24 months and 8 years corrected age. |
| Growth | Length and head circumference (HC). |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Tom Stiris, MD, ass prof | Departement of Neonatal Intensive care, Oslo University Hospital | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Oslo University Hospital | Oslo | Norway |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 40580806 | Derived | Gunnarsdottir G, Rossholt ME, Nordvik T, Wendel K, Aas MF, Skarbo AB, Aulie VS, Stiris T, Ramm-Pettersen A, Pfeiffer HC, Moltu SJ. High dose arachidonic and docosahexaenoic acid in very preterm infants and neurodevelopment at 2 years - A double-blind randomized controlled trial. Clin Nutr. 2025 Aug;51:198-205. doi: 10.1016/j.clnu.2025.05.019. Epub 2025 Jun 4. | |
| 38061271 |
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Data will be available within 6 months of study completion
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| ID | Term |
|---|---|
| D047928 | Premature Birth |
| ID | Term |
|---|---|
| D007752 | Obstetric Labor, Premature |
| D007744 | Obstetric Labor Complications |
| D011248 | Pregnancy Complications |
| D005261 | Female Urogenital Diseases and Pregnancy Complications |
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Double-blind, randomized-controlled. Parallel group, single center trial
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| MCT-oil |
| Dietary Supplement |
Supplementation with medium chain fatty acids |
|
| Length and HC will be recorded until 36 weeks PMA and at 3, 6, 12 and 24 months and 8 years corrected age. |
| Body composition | Body composition will be assessed using PEA POD, an air displacement plethysmography system and Dexa Scan. | At 36 weeks PMA, 3 months and 2 years corrected age |
| Neonatal morbidities associated with inflammation | Bronchopulmonary dysplasia (BPD), retinopathy of prematurity (ROP), necrotizing enterocolitis (NEC), white matter injury (WMI) of the brain, and late onset septicemia | From birth til 36 weeks PMA |
| Cerebral Background Activity evaluated by Electroencephalogram (EEG) | EEG maturational changes will be examined as a function of time and as a function of gestational age | First week of life, 36 weeks PMA and 2 years corrected age (CA) |
| Neurodevelopment assessed by standardized motor and cognitive tests | Evaluation of psychomotor development by performing Bayley III and a standardized neurological examination | 2 years corrected age (CA) |
| Lung function evaluated by tidal breathing measurements | Tidal breathing measurements include tidal volume, respiratory rate, minute ventilation and fraction of expiratory time to peak tidal expiratory flow to total expiratory time | 36 weeks PMA, 3 months and 2 years CA |
| Cardiovascular Health assessed by echocardiography | Echocardiography will be used to follow the transition from fetal to completed neonatal circulation, to measure superior vena cava flow, and to study mycardial function by the use of conventional two-dimensional echocardiography and tissue Doppler imaging. | First week of life, 2nd week of life, at 36 weeks PMA and 2 years CA |
| Blood pressure | Measurements of systolic, diastolic and mean pressure | First week of life and at 36 weeks PMA and 2 years CA |
| Fatty acid (FA) profiles in blood | Repeated dried blood spots (DBS) samples with approximately 10 µL blood will be collected for FA analyses. These analyses are important for assessing efficacy and protocol compliance. We will also collect 10 µL of fullblood for assessment of total lipid profile (Lipidomics). | From birth until 36 weeks PMA |
| Markers of inflammation | Inflammation panels will be used to assess markers of inflammation in fullblood and sputum | From birth until 36 weeks PMA |
| Markers of metabolic status | Metabolic pathway analyses (http://omictools.com/metabolic-pathways-category) will be performed to analyse and describe the metabolic conditions of the infants during hospitalization. Metabolites outside the standard clinical chemistry parameters will also be investigated ("untargeted metabolomics). Metabolomics will be performed by the use of dried blood spot samples | From birth until 36 weeks PMA |
| Markers of nutritional status in blood | The concentrations of electrolytes, minerals, albumin, alkaline phosphatase, vitamin A and D will be assessed regularly during hospitalization | From birth until 36 weeks PMA |
| Micronutrient content in urine | Spot urine will be obtained regularly to study the changes in electrolyte- and mineral homeostasis during the first week of life as well as during the phase of steady growth | From birth until 36 weeks PMA |
| Evaluation of nutrient composition of expressed breast milk | Repeated samples of breast milk will be collected for FA analyses, macronutrient content and vitamin A | From birth until 36 weeks PMA |
| Gut microbiota | Repeated samples of feces will be used to study the early fecal microbiota | From birth until 36 weeks PMA |
| Inflammatory markers in sputum | We will analyze the Expression of a standardized panel of inflammatory markers in collected laryngeal or tracheal secretion | From birth until 36 weeks PMA |
| Moltu SJ, Nordvik T, Rossholt ME, Wendel K, Chawla M, Server A, Gunnarsdottir G, Pripp AH, Domellof M, Bratlie M, Aas M, Huppi PS, Lapillonne A, Beyer MK, Stiris T, Maximov II, Geier O, Pfeiffer H. Arachidonic and docosahexaenoic acid supplementation and brain maturation in preterm infants; a double blind RCT. Clin Nutr. 2024 Jan;43(1):176-186. doi: 10.1016/j.clnu.2023.11.037. Epub 2023 Nov 29. |
| 37856920 | Derived | Rossholt ME, Bratlie M, Wendel K, Aas MF, Gunnarsdottir G, Fugelseth D, Pripp AH, Domellof M, Stordal K, Stiris T, Moltu SJ. Effect of arachidonic and docosahexaenoic acid supplementation on quality of growth in preterm infants: A secondary analysis of a randomized controlled trial. Clin Nutr. 2023 Dec;42(12):2311-2319. doi: 10.1016/j.clnu.2023.10.005. Epub 2023 Oct 17. |
| 36473425 | Derived | Wendel K, Aas MF, Gunnarsdottir G, Rossholt ME, Bratlie M, Nordvik T, Landsend ECS, Fugelseth D, Domellof M, Pripp AH, Stiris T, Moltu SJ. Effect of arachidonic and docosahexaenoic acid supplementation on respiratory outcomes and neonatal morbidities in preterm infants. Clin Nutr. 2023 Jan;42(1):22-28. doi: 10.1016/j.clnu.2022.11.012. Epub 2022 Nov 17. |
| 34392310 | Derived | Hortensius LM, Hellstrom W, Savman K, Heckemann RA, Bjorkman-Burtscher IM, Groenendaal F, Andersson MX, Nilsson AK, Tataranno ML, van Elburg RM, Hellstrom A, Benders MJNL. Serum docosahexaenoic acid levels are associated with brain volumes in extremely preterm born infants. Pediatr Res. 2021 Dec;90(6):1177-1185. doi: 10.1038/s41390-021-01645-w. Epub 2021 Aug 14. |
| 33407269 | Derived | Wendel K, Pfeiffer HCV, Fugelseth DM, Nestaas E, Domellof M, Skalhegg BS, Elgstoen KBP, Rootwelt H, Pettersen RD, Pripp AH, Stiris T, Moltu SJ; ImNuT Collaboration Group. Effects of nutrition therapy on growth, inflammation and metabolism in immature infants: a study protocol of a double-blind randomized controlled trial (ImNuT). BMC Pediatr. 2021 Jan 7;21(1):19. doi: 10.1186/s12887-020-02425-x. |
| D000091642 | Urogenital Diseases |