Evidence on docosahexaenoic acid and arachidonic acid supplementation for preterm infants.

PURPOSE OF REVIEW: For many decades, docosahexaenoic acid (DHA) supplementation was tested in premature infants to achieve an intake equivalent to the average level in breast milk, but this approach has led to conflicting results in terms of development and health outcomes. Higher doses of DHA closer to fetal accumulation may be needed. RECENT FINDINGS: The efficacy of DHA supplementation for preterm infants at a dose equivalent to the estimated fetal accumulation rate is still under investigation, but this may be a promising approach, especially in conjunction with arachidonic acid supplementation. Current data suggest benefit for some outcomes, such as brain maturation, long-term cognitive function, and the prevention of retinopathy of prematurity. The possibility that supplementation with highly unsaturated oils increases the risk of neonatal morbidities should not be ruled out, but current meta-analyzes do not support a significant risk. SUMMARY: The published literature supports a DHA intake in preterm infants that is closer to the fetal accumulation rate than the average breast milk content. Supplementation with DHA at this level in combination with arachidonic acid is currently being investigated and appears promising.

Arachidonic and docosahexaenoic acid supplementation and brain maturation in preterm infants; a double blind RCT.

BACKGROUND: Arachidonic acid (ARA) and docosahexaenoic acid (DHA) are important structural components of neural cellular membranes and possess anti-inflammatory properties. Very preterm infants are deprived of the enhanced placental supply of these fatty acids, but the benefit of postnatal supplementation on brain development is uncertain. The aim of this study was to test the hypothesis that early enteral supplementation with ARA and DHA in preterm infants improves white matter (WM) microstructure assessed by diffusion-weighted MRI at term equivalent age. METHODS: In this double-blind, randomized controlled trial, infants born before 29 weeks gestational age were allocated to either 100 mg/kg ARA and 50 mg/kg DHA (ARA:DHA group) or medium chain triglycerides (control). Supplements were started on the second day of life and provided until 36 weeks postmenstrual age. The primary outcome was brain maturation assessed by diffusion tensor imaging (DTI) using Tract-Based Spatial Statistics (TBSS) analysis. RESULTS: We included 120 infants (60 per group) in the trial; mean (range) gestational age was 26+3 (22+6 - 28+6) weeks and postmenstrual age at scan was 41+3 (39+1 - 47+0) weeks. Ninety-two infants underwent MRI imaging, and of these, 90 had successful T1/T2 weighted MR images and 74 had DTI data of acceptable quality. TBSS did not show significant differences in mean or axial diffusivity between the groups, but demonstrated significantly higher fractional anisotropy in several large WM tracts in the ARA:DHA group, including corpus callosum, the anterior and posterior limb of the internal capsula, inferior occipitofrontal fasciculus, uncinate fasciculus, and the inferior longitudinal fasciculus. Radial diffusivity was also significantly lower in several of the same WM tracts in the ARA:DHA group. CONCLUSION: This study suggests that supplementation with ARA and DHA at doses matching estimated fetal accretion rates improves WM maturation compared to control treatment, but further studies are needed to ascertain any functional benefit. CLINICAL TRIAL REGISTRATION: www. CLINICALTRIALS: gov; ID:NCT03555019.

Effects of nutrition therapy on growth, inflammation and metabolism in immature infants: a study protocol of a double-blind randomized controlled trial (ImNuT).

BACKGROUND: Current nutritional management of infants born very preterm results in significant deficiency of the essential fatty acids (FAs) arachidonic acid (ARA) and docosahexaenoic acid (DHA). The impact of this deficit on brain maturation and inflammation mediated neonatal morbidities are unknown. The aim of this study is to determine whether early supply of ARA and DHA improves brain maturation and neonatal outcomes in infants born before 29 weeks of gestation. METHODS: Infants born at Oslo University Hospital are eligible to participate in this double-blind randomized controlled trial. Study participants are randomized to receive an enteral FA supplement of either 0.4 ml/kg MCT-oil™ (medium chain triglycerides) or 0.4 ml/kg Formulaid™ (100 mg/kg of ARA and 50 mg/kg of DHA). The FA supplement is given from the second day of life to 36 weeks' postmenstrual age (PMA). The primary outcome is brain maturation assessed by Magnetic Resonance Imaging (MRI) at term equivalent age. Secondary outcomes include quality of growth, incidence of neonatal morbidities, cardiovascular health and neuro-development. Target sample size is 120 infants (60 per group), this will provide 80% power to detect a 0.04 difference in mean diffusivity (MD, mm2/sec) in major white matter tracts on MRI. DISCUSSION: Supplementation of ARA and DHA has the potential to improve brain maturation and reduce inflammation related diseases. This study is expected to provide valuable information for future nutritional guidelines for preterm infants. TRIAL REGISTRATION: Clinicaltrials.gov ID: NCT03555019 . Registered 4 October 2018- Retrospectively registered.

Enhanced nutrient supply to very low birth weight infants is associated with higher blood amino acid concentrations and improved growth.

BACKGROUND & AIMS: Customized nutrient supply is vital to ensure optimal growth among very low birth weight infants (birth weight < 1500 g). The supply of amino acids is especially important due to their impact on protein synthesis and growth. The objectives of this study were to evaluate the impact of enhanced nutrition on growth, blood concentrations of amino acids, and explore possible associations between amino acid concentrations and common neonatal morbidities. We hypothesized higher amino acids levels and growth velocity among infants on enhanced nutrient supply. METHODS: This randomized controlled trial was performed in three university neonatal intensive care units in Oslo, Norway. Fifty very low birth weight infants were randomized to a control or intervention group. Within 24 h after birth, infants in the intervention group received enhanced supply of energy, amino acids, lipids, long-chain polyunsaturated fatty acids and vitamin A, whereas the control group received a standard nutrient supply. The intervention continued until 52 weeks postmenstrual age or until a body weight of 5.5 kg was reached. Amino acid analyses were performed at birth, day 3, 5 weeks of age and 5 months corrected age. Detailed information about nutrient intake, morbidities, blood amino acid concentrations and growth velocity were collected from 44 infants (6 infants excluded). High-performance liquid chromatography was used for amino acid analysis. RESULTS: The intervention group (n = 23) received higher supply of proteins, with higher blood concentrations of amino acids measured at 5 weeks of age, and improved growth velocity (mean 17.4 vs 14.3 g/kg/day, p < 0.001) at 36 weeks postmenstrual age, compared to the control group (n = 21). The correlation between concentrations of branched chain amino acids (leucine, isoleucine and valine) and growth was stronger and more positive among infants: a) in the control group (correlation coefficient ≥ 0.68, p ≤ 0.004); b) born with birth weight appropriate for gestational age (correlation coefficient ≥ 0.53, p ≤ 0.009) and c) not diagnosed with septicemia (correlation coefficient ≥ 0.63, p ≤ 0.005). CONCLUSION: Enhanced nutrient supply to very low birth weight infants led to higher blood amino acid concentrations and improved growth. The correlations between amino acid concentrations and growth velocity were weaker in the intervention group as compared to the control group. This could reflect an upper threshold for protein synthesis and growth with our intervention, whereas a potential for further growth with increasing amino acid supply was possible for the control group. CLINICAL TRIAL REGISTRATION NO: NCT01103219.

Serum Magnesium Levels in Preterm Infants Are Higher Than Adult Levels: A Systematic Literature Review and Meta-Analysis.

Magnesium (Mg) is an essential mineral in the body, impacting the synthesis of biomacromolecules, bone matrix development, energy production, as well as heart, nerve, and muscle function. Although the importance of Mg is evident, reference values for serum Mg (sMg) in pediatric patients (more specifically, in neonates) are not well established. This systematic literature review and meta-analysis (using 47 eligible studies) aims to quantify normal and tolerable ranges of sMg concentrations during the neonatal period and to highlight the factors influencing Mg levels and the importance of regulating sMg levels during pregnancy and birth. In newborns without Mg supplementation during pregnancy, magnesium levels at birth (0.76 (95% CI: 0.52, 0.99) mmol/L) were similar to that of mothers during pregnancy (0.74 (95% CI: 0.43, 1.04) mmol/L), but increased during the first week of life (0.91 (95% CI: 0.55, 1.26) mmol/L) before returning to adult levels. This pattern was also seen in newborns with Mg supplementation during pregnancy, where the average was 1.29 (95% CI: 0.50, 2.08) mmol/L at birth and 1.44 (95% CI: 0.61, 2.27) mmol/L during the first week of life. Factors influencing these levels include prenatal Mg supplementation, gestational age, birth weight, renal maturity/function, and postnatal Mg intake. Elevated Mg levels (>2.5 mmol/L) have been associated with an increased risk of mortality, admission into intensive care, hypotonia, hypotension, and respiratory depression but sMg concentrations up to 2.0 mmol/L appear to be well tolerated in neonates, requiring adequate survey and minimal intervention.

Long-Chain Polyunsaturated Fatty Acids and Clinical Outcomes of Preterm Infants.

Long-chain polyunsaturated fatty acids (LCPUFAs) play specific roles during the perinatal period and are very important nutrients to consider. The possible effects of LCPUFAs, particularly docosahexaenoic acid (DHA), on various clinical outcomes of preterm infants are discussed in this paper. Since DHA accumulates in the central nervous system during development, a lot of attention has focused on the effects of DHA on neurodevelopment. Experimental studies as well as recent clinical trials show that providing larger amounts of DHA than currently and routinely provided is associated with better neurological outcomes at 18 months to 2 years. This early advantage, however, does not seem to translate into detectable change in visual and neurodevelopmental outcomes or behavior when assessed in childhood. There is growing evidence that, in addition to effects on development, omega-3 LCPUFAs may reduce the incidence or severity of neonatal morbidities by affecting different steps of the immune and anti-inflammatory response. Studies in preterm infants suggest that the omega-3 LCPUFAs may play a significant role by reducing the risk of bronchopulmonary dysplasia, necrotizing enterocolitis and possibly retinopathy of prematurity and sepsis. Overall, evidence is increasing to support the benefits of high-dose DHA for various health outcomes of preterm infants. These findings are of major clinical relevance mainly because infants born preterm are at particularly high risk for a nutritional deficit in omega-3 fatty acids, predisposing to adverse neonatal outcomes. Further studies are warranted to address these issues as well as to more precisely determine the LCPUFA requirement in order to favor the best possible outcomes of preterm infants.

Improved Visual Perception in Very Low Birth Weight Infants on Enhanced Nutrient Supply.

BACKGROUND: Optimal nutrient supply to very low birth weight (VLBW: BW <1,500 g) infants is important for growth and neurodevelopment. Growth restriction is common among these infants and may be associated with neurocognitive impairments. OBJECTIVES: To compare an enhanced nutrient supply to a routine supply given to VLBW infants and to evaluate the effects on visual perception of global form and motion measured by visual event-related potentials (VERP). METHODS: A total of 50 VLBW infants were randomized to an intervention group that received an increased supply of energy, protein, fat, essential fatty acids, and vitamin A or a control group that received standard nutritional care. At 5 months' corrected age the infants were examined using VERP to investigate the responses to global form and motion. VERP were analysed at the first (f1) and third (f3) harmonics of the stimulus frequency. RESULTS: Data from 31 subjects were eligible for analysis. The motion VERP responses for the f1 and f3 components were stronger in the area near the posterior midline region in the intervention group compared to the controls in the group analyses (p = 0.02 and p = 0.001, respectively). CONCLUSION: The results showed a more consistent response to global motion among infants receiving enhanced nutrition. The intervention may have improved visual perception of global motion.

Enhanced feeding in very-low-birth-weight infants may cause electrolyte disturbances and septicemia--a randomized, controlled trial.

BACKGROUND & AIMS: High supply of protein and energy has been introduced to very-low-birth-weight infants to improve growth and cognitive development. The aim of this study was to compare two different feeding strategies on postnatal growth and clinical outcome during neonatal hospitalization. METHODS: Fifty very-low-birth-weight infants were randomized to either an enhanced or a standard feeding protocol within 24 h after birth. Chi-square and T-tests were applied. RESULTS: First week protein, fat and energy supply was significantly higher in the intervention group compared to the control group (all P < 0.001). After inclusion of 50 patients we observed a higher occurrence of septicemia in the intervention group, 63% vs. 29% (P = 0.02), and no more patients were included. The infants in the intervention group demonstrated improved postnatal growth, but they also disclosed significant electrolyte deviations during the first week of life with hypophosphatemia, hypokalemia and hypercalcemia. First week phosphate nadir was lower in the infants experiencing septicemia (1.23 (0.50) mmol/L) as compared to the infants without (1.61 (0.61) mmol/L) (P = 0.03). CONCLUSION: Our study implies that enhanced feeding may induce electrolyte imbalances in VLBW infants, and that deleterious side effects similar to those seen in refeeding syndrome may occur. ClinicalTrials.gov, number NCT01103219 and the EudraCT number is 2010-020464-38.