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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
SUPPORTIVE_CARE
Masking
QUADRUPLE
Enrollment
121
Oslo University Hospital
Oslo, Norway
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
Time frame: 40 weeks postmenstrual age (PMA)
Weight gain
Weight measurements, including weight nadir.
Time frame: 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).
Time frame: 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.
Time frame: 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
Time frame: 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
Time frame: First week of life, 36 weeks PMA and 2 years corrected age (CA)
Neurodevelopment assessed by standardized motor and cognitive tests
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Evaluation of psychomotor development by performing Bayley III and a standardized neurological examination
Time frame: 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
Time frame: 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.
Time frame: 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
Time frame: 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).
Time frame: From birth until 36 weeks PMA
Markers of inflammation
Inflammation panels will be used to assess markers of inflammation in fullblood and sputum
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: From birth until 36 weeks PMA
Gut microbiota
Repeated samples of feces will be used to study the early fecal microbiota
Time frame: 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
Time frame: From birth until 36 weeks PMA