Arachidonic acid and docosahexaenoic acid levels correlate with the inflammation proteome in extremely preterm infants.

BACKGROUND & AIM: Clinical trials supplementing the long-chain polyunsaturated fatty acids (LCPUFAs) docosahexaenoic acid (DHA) and arachidonic acid (AA) to preterm infants have shown positive effects on inflammation-related morbidities, but the molecular mechanisms underlying these effects are not fully elucidated. This study aimed to determine associations between DHA, AA, and inflammation-related proteins during the neonatal period in extremely preterm infants. METHODS: A retrospective exploratory study of infants (n = 183) born below 28 weeks gestation from the Mega Donna Mega trial, a randomized multicenter trial designed to study the effect of DHA and AA on retinopathy of prematurity. Serial serum samples were collected after birth until postnatal day 100 (median 7 samples per infant) and analyzed for phospholipid fatty acids and proteins using targeted proteomics covering 538 proteins. Associations over time between LCPUFAs and proteins were explored using mixed effect modeling with splines, including an interaction term for time, and adjusted for gestational age, sex, and center. RESULTS: On postnatal day one, 55 proteins correlated with DHA levels and 10 proteins with AA levels. Five proteins were related to both fatty acids, all with a positive correlation. Over the first 100 days after birth, we identified 57 proteins to be associated with DHA and/or AA. Of these proteins, 41 (72%) related to inflammation. Thirty-eight proteins were associated with both fatty acids and the overall direction of association did not differ between DHA and AA, indicating that both LCPUFAs similarly contribute to up- and down-regulation of the preterm neonate inflammatory proteome. Primary examples of this were the inflammation-modulating cytokines IL-6 and CCL7, both being negatively related to levels of DHA and AA in the postnatal period. CONCLUSIONS: This study supports postnatal non-antagonistic and potentially synergistic effects of DHA and AA on the inflammation proteome in preterm infants, indicating that supplementation with both fatty acids may contribute to limiting the disease burden in this vulnerable population. CLINICAL REGISTRATION NUMBER: ClinicalTrials.gov (NCT03201588).

Enteral supplementation with arachidonic and docosahexaenoic acid and pulmonary outcome in extremely preterm infants.

Enteral supplementation with arachidonic acid (AA) and docosahexaenoic acid (DHA) in extremely preterm infants has shown beneficial effects on retinopathy of prematurity and pulmonary outcome whereas exclusive DHA supplementation has been associated with increased pulmonary morbidity. This secondary analysis evaluates pulmonary outcome in 204 extremely preterm infants, randomized to receive AA (100 mg/kg/day) and DHA (50 mg/kg/day) enterally from birth until term age or standard care. Pulmonary morbidity was primarily assessed based on severity of bronchopulmonary dysplasia (BPD). Serum levels of AA and DHA during the first 28 days were analysed in relation to BPD. Supplementation with AA:DHA was not associated with increased BPD severity, adjusted OR 1.48 (95 % CI 0.85-2.61), nor with increased need for respiratory support at post menstrual age 36 weeks or duration of oxygen supplementation. Every 1 % increase in AA was associated with a reduction of BPD severity, adjusted OR 0.73 (95 % CI 0.58-0.92). In conclusion, in this study, with limited statistical power, enteral supplementation with AA:DHA was not associated with an increased risk of pulmonary morbidity, but higher levels of AA were associated with less severe BPD. Whether AA or the combination of AA and DHA have beneficial roles in the immature lung needs further research.

Modification of serum fatty acids in preterm infants by parenteral lipids and enteral docosahexaenoic acid/arachidonic acid: A secondary analysis of the Mega Donna Mega trial.

BACKGROUND & AIM: Preterm infants risk deficits of long-chain polyunsaturated fatty acids (LCPUFAs) that may contribute to morbidities and hamper neurodevelopment. We aimed to determine longitudinal serum fatty acid profiles in preterm infants and how the profiles are affected by enteral and parenteral lipid sources. METHODS: Cohort study analyzing fatty acid data from the Mega Donna Mega study, a randomized control trial with infants born <28 weeks of gestation (n = 204) receiving standard nutrition or daily enteral lipid supplementation with arachidonic acid (AA):docosahexaenoic acid (DHA) (100:50 mg/kg/day). Infants received an intravenous lipid emulsion containing olive oil:soybean oil (4:1). Infants were followed from birth to postmenstrual age 40 weeks. Levels of 31 different fatty acids from serum phospholipids were determined by GC-MS and reported in relative (mol%) and absolute concentration (µmol l-1) units. RESULTS: Higher parenteral lipid administration resulted in lower serum proportion of AA and DHA relative to other fatty acids during the first 13 weeks of life (p < 0.001 for the 25th vs the 75th percentile). The enteral AA:DHA supplement increased the target fatty acids with little impact on other fatty acids. The absolute concentration of total phospholipid fatty acids changed rapidly in the first weeks of life, peaking at day 3, median (Q1-Q3) 4452 (3645-5466) µmol l-1, and was positively correlated to the intake of parenteral lipids. Overall, infants displayed common fatty acid trajectories over the study period. However, remarkable differences in fatty acid patterns were observed depending on whether levels were expressed in relative or absolute units. For example, the relative levels of many LCPUFAs, including DHA and AA, declined rapidly after birth while their absolute concentrations increased in the first week of life. For DHA, absolute levels were significantly higher compared to cord blood from day 1 until postnatal week 16 (p < 0.001). For AA, absolute postnatal levels were lower compared to cord blood from week 4 throughout the study period (p < 0.05). CONCLUSIONS: Our data show that parenteral lipids aggravate the postnatal loss of LCPUFAs seen in preterm infants and that serum AA available for accretion is below that in utero. Further research is needed to establish optimal postnatal fatty acid supplementation and profiles in extremely preterm infants to promote development and long-term health. CLINICAL TRIAL REGISTRY: ClinicalTrials.gov, identifier: NCT03201588.

Effect of Enteral Lipid Supplement on Severe Retinopathy of Prematurity: A Randomized Clinical Trial.

Importance: Lack of arachidonic acid (AA) and docosahexaenoic acid (DHA) after extremely preterm birth may contribute to preterm morbidity, including retinopathy of prematurity (ROP). Objective: To determine whether enteral supplementation with fatty acids from birth to 40 weeks' postmenstrual age reduces ROP in extremely preterm infants. Design, Setting, and Participants: The Mega Donna Mega trial, a randomized clinical trial, was a multicenter study performed at 3 university hospitals in Sweden from December 15, 2016, to December 15, 2019. The screening pediatric ophthalmologists were masked to patient groupings. A total of 209 infants born at less than 28 weeks' gestation were tested for eligibility, and 206 infants were included. Efficacy analyses were performed on as-randomized groups on the intention-to-treat population and on the per-protocol population using as-treated groups. Statistical analyses were performed from February to April 2020. Interventions: Infants received either supplementation with an enteral oil providing AA (100 mg/kg/d) and DHA (50 mg/kg/d) (AA:DHA group) or no supplementation within 3 days after birth until 40 weeks' postmenstrual age. Main Outcomes and Measures: The primary outcome was severe ROP (stage 3 and/or type 1). The secondary outcomes were AA and DHA serum levels and rates of other complications of preterm birth. Results: A total of 101 infants (58 boys [57.4%]; mean [SD] gestational age, 25.5 [1.5] weeks) were included in the AA:DHA group, and 105 infants (59 boys [56.2%]; mean [SD] gestational age, 25.5 [1.4] weeks) were included in the control group. Treatment with AA and DHA reduced severe ROP compared with the standard of care (16 of 101 [15.8%] in the AA:DHA group vs 35 of 105 [33.3%] in the control group; adjusted relative risk, 0.50 [95% CI, 0.28-0.91]; P = .02). The AA:DHA group had significantly higher fractions of AA and DHA in serum phospholipids compared with controls (overall mean difference in AA:DHA group, 0.82 mol% [95% CI, 0.46-1.18 mol%]; P < .001; overall mean difference in control group, 0.13 mol% [95% CI, 0.01-0.24 mol%]; P = .03). There were no significant differences between the AA:DHA group and the control group in the rates of bronchopulmonary dysplasia (48 of 101 [47.5%] vs 48 of 105 [45.7%]) and of any grade of intraventricular hemorrhage (43 of 101 [42.6%] vs 42 of 105 [40.0%]). In the AA:DHA group and control group, respectively, sepsis occurred in 42 of 101 infants (41.6%) and 53 of 105 infants (50.5%), serious adverse events occurred in 26 of 101 infants (25.7%) and 26 of 105 infants (24.8%), and 16 of 101 infants (15.8%) and 13 of 106 infants (12.3%) died. Conclusions and Relevance: This study found that, compared with standard of care, enteral AA:DHA supplementation lowered the risk of severe ROP by 50% and showed overall higher serum levels of both AA and DHA. Enteral lipid supplementation with AA:DHA is a novel preventive strategy to decrease severe ROP in extremely preterm infants. Trial Registration: ClinicalTrials.gov Identifier: NCT03201588.

Computer-aided nutrition - Effects on nutrition and growth in preterm infants <32 weeks of gestation.

BACKGROUND & AIMS: Preterm infants are often discharged from the NICU with suboptimal growth. The aim of our intervention study was to determine if a computer-aided nutrition calculation program could help to optimise the nutrition and secondary improve the growth of preterm infants. METHODS: Intake of macro- and micronutrients and anthropometric data was collected in 78 preterm infants with GA ≤32+0 from birth to postnatal week 7. The nutrition of 43 preterm infants was ordinated with help of the program Nutrium™â€‹ (IG). Before the introduction of the program 35 consecutive preterm infants served as control group (CG). Their data were collected in retrospect. RESULTS: Amino acid, carbohydrate, fluid intake and total energy intake were statistically different at all time points. Fatty acid intake was statistically different expect for week 2 and 4. Similar differences were found for magnesium, calcium and phosphorus, zinc, copper and selenium. In contrast vitamin intake was higher in the control group. At birth there were no differences between the groups with respect to anthropometric data. Weight, length and head circumference (HC) SDS decreased in both groups from birth to day 28 of life (CG -1.2 SDS; -1.2 SDS; -0.8 SDS vs IG -0.9 SDS; -0.8 SDS; -0.4 SDS). The infants in the CG showed until discharge a partial catch-up but remained below birth SDS for weight and length (-0.5 SDS; -0.9 SDS). In the IG, infants reached birth values for weight and length (-0.1 SDS; 0 SDS). For HC both groups showed similar values at the time point for birth and discharge (CG +0.3 SDS vs IG +0.5 SDS). CONCLUSION: By using a computer-aided nutrition calculation program better postnatal growth was achieved. Nutritional intake was increased in respect to nearly all micro- and macronutrients. There were no adverse effects. In contrast there was a tendency of decreased incidence of BPD, infection rate and PDA.