A Randomized Trial of Parenteral Nutrition Using a Mixed Lipid Emulsion Containing Fish Oil in Infants of Extremely Low Birth Weight: Neurodevelopmental Outcome at 12 and 24 Months Corrected Age, A Secondary Outcome Analysis

      Objective

      To examine whether parenteral nutrition using a mixed lipid emulsion containing fish oil improves the neurodevelopmental outcomes of extremely low birth weight infants.

      Study design

      The study is a secondary outcome analysis of a double-blind randomized trial of 230 extremely low birth weight infants performed at a single level IV neonatal care unit (Medical University Vienna; June 2012 to June 2015). Participants received either a mixed lipid emulsion composed of soybean oil, medium chain triglycerides, olive oil, and fish oil, or a soybean oil-based lipid emulsion for parenteral nutrition. Neurodevelopment of study participants was assessed at 12 and 24 months corrected age (August 2013 to October 2017) using the Bayley Scales of Infant-Toddler Development, third edition.

      Results

      At discharge, 206 of the 230 study participants were eligible. At 12 and 24 months corrected age, 174 of 206 (85%) and 164 of 206 (80%) infants were evaluated. At 12 months, there was no significant difference in cognitive (mixed lipid: median, 95 [IQR, 85-101]; soybean oil: median, 95 [IQR, 85-100]; P = .71), language (mixed lipid: median, 86 [IQR, 77-94], soybean oil: median, 89 [IQR, 79-94]; P = .48), or motor scores (mixed lipid: median, 88 [IQR, 76-94], soybean oil: median, 88 [IQR, 79-94]; P = .69). At 24 months, there was again no significant difference in cognitive (mixed lipid: median, 95 [IQR, 80-105], soybean oil: median, 95 [IQR, 90-105]; P = .17), language (mixed lipid: median, 89 [IQR, 75-97], soybean oil 89 [IQR, 77-100]; P = .54), and motor scores (mixed lipid: median, 94 [IQR, 82-103], soybean oil: median, 94 [IQR, 85-103]; P = .53).

      Conclusions

      Parenteral nutrition using a mixed lipid emulsion containing fish oil did not improve neurodevelopment of extremely low birth weight infants at 12 and 24 months corrected age.

      Trial registration

      Keywords

      Abbreviations:

      ARA ( Arachidonic acid), Bayley-III ( Bayley Scales of Infant and Toddler Development, third edition), DHA ( Docosahexaenoic acid), ELBW ( Extremely low birth weight), EPA ( Eicosapentaenoic acid), GMFCS ( Gross Motor Function Classification System), LC-PUFA ( Long-chain polyunsaturated fatty acid)
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      References

        • Mercier C.E.
        • Dunn M.S.
        • Ferrelli K.R.
        • Howard D.B.
        • Soll R.F.
        • Vermont Oxford Network EIF-USG
        Neurodevelopmental outcome of extremely low birth weight infants from the Vermont Oxford network: 1998-2003.
        Neonatology. 2010; 97: 329-338
        • Joosten K.
        • Embleton N.
        • Yan W.
        • Senterre T.
        ESPGHAN/ESPEN/ESPR/CSPEN Working Group on Pediatric Parenteral Nutrition. ESPGHAN/ESPEN/ESPR guidelines on pediatric parenteral nutrition: energy.
        Clin Nutr. 2018; 37: 2309-2314
        • Chan S.H.
        • Johnson M.J.
        • Leaf A.A.
        • Vollmer B.
        Nutrition and neurodevelopmental outcomes in preterm infants: a systematic review.
        Acta Paediatr. 2016; 105: 587-599
        • Harris W.S.
        • Baack M.L.
        Beyond building better brains: bridging the docosahexaenoic acid (DHA) gap of prematurity.
        J Perinatol. 2015; 35: 1-7
        • Koletzko B.
        • Agostoni C.
        • Carlson S.E.
        • Clandinin T.
        • Hornstra G.
        • Neuringer M.
        • et al.
        Long chain polyunsaturated fatty acids (LC-PUFA) and perinatal development.
        Acta Paediatr. 2001; 90: 460-464
        • Lapillonne A.
        • Jensen C.L.
        Reevaluation of the DHA requirement for the premature infant.
        Prostaglandins Leukot Essent Fatty Acids. 2009; 81: 143-150
        • Smith S.L.
        • Rouse C.A.
        Docosahexaenoic acid and the preterm infant.
        Matern Health Neonatol Perinatol. 2017; 3: 22
        • Repa A.
        • Binder C.
        • Thanhaeuser M.
        • Kreissl A.
        • Pablik E.
        • Huber-Dangl M.
        • et al.
        A mixed lipid emulsion for prevention of parenteral nutrition associated cholestasis in extremely low birth weight infants: a randomized clinical trial.
        J Pediatr. 2018; 194: 87-93.e1
        • Binder C.
        • Giordano V.
        • Thanhaeuser M.
        • Kreissl A.
        • Huber-Dangl M.
        • Longford N.
        • et al.
        A mixed lipid emulsion containing fish oil and its effect on electrophysiological brain maturation in infants of extremely low birth weight: a secondary analysis of a randomized clinical trial.
        J Pediatr. 2019; 211: 46-53
        • Rayyan M.
        • Devlieger H.
        • Jochum F.
        • Allegaert K.
        Short-term use of parenteral nutrition with a lipid emulsion containing a mixture of soybean oil, olive oil, medium-chain triglycerides, and fish oil: a randomized double-blind study in preterm infants.
        JPEN J Parenter Enteral Nutr. 2012; 36: 81S-94S
        • D'Ascenzo R.
        • Savini S.
        • Biagetti C.
        • Bellagamba M.P.
        • Marchionni P.
        • Pompilio A.
        • et al.
        Higher docosahexaenoic acid, lower arachidonic acid and reduced lipid tolerance with high doses of a lipid emulsion containing 15% fish oil: a randomized clinical trial.
        Clin Nutr. 2014; 33: 1002-1009
        • Klebermass-Schrehof K.
        • Wald M.
        • Schwindt J.
        • Grill A.
        • Prusa A.R.
        • Haiden N.
        • et al.
        Less invasive surfactant administration in extremely preterm infants: impact on mortality and morbidity.
        Neonatology. 2013; 103: 252-258
        • Fenton T.R.
        • Kim J.H.
        A systematic review and meta-analysis to revise the Fenton growth chart for preterm infants.
        BMC Pediatr. 2013; 13: 59
        • Bayley N.B.
        Scales of Infant and Toddler Development - Third Edition.
        J Psychoeduc Assess. 2006; 25: 180-198
        • Palisano R.
        • Rosenbaum P.
        • Walter S.
        • Russell D.
        • Wood E.
        • Galuppi B.
        Development and reliability of a system to classify gross motor function in children with cerebral palsy.
        Dev Med Child Neurol. 1997; 39: 214-223
        • Zhao Y.
        • Wu Y.
        • Pei J.
        • Chen Z.
        • Wang Q.
        • Xiang B.
        Safety and efficacy of parenteral fish oil-containing lipid emulsions in premature neonates.
        J Pediatr Gastroenterol Nutr. 2015; 60: 708-716
        • Anez-Bustillos L.
        • Dao D.T.
        • Baker M.A.
        • Fell G.L.
        • Puder M.
        • Gura K.M.
        Intravenous fat emulsion formulations for the adult and pediatric patient: understanding the differences.
        Nutr Clin Pract. 2016; 31: 596-609
        • Tanaka K.
        • Farooqui A.A.
        • Siddiqi N.J.
        • Alhomida A.S.
        • Ong W.Y.
        Effects of docosahexaenoic Acid on neurotransmission.
        Biomol Ther (Seoul). 2012; 20: 152-157
        • Georgieff M.K.
        Nutrition and the developing brain: nutrient priorities and measurement.
        Am J Clin Nutr. 2007; 85: 614S-620S
        • Calderon F.
        • Kim H.Y.
        Docosahexaenoic acid promotes neurite growth in hippocampal neurons.
        J Neurochem. 2004; 90: 979-988
        • Dai Y.J.
        • Sun L.L.
        • Li M.Y.
        • Ding C.L.
        • Su Y.C.
        • Sun L.J.
        • et al.
        Comparison of formulas based on lipid emulsions of olive oil, soybean oil, or several oils for parenteral nutrition: a systematic review and meta-analysis.
        Adv Nutr. 2016; 7: 279-286
        • Kuipers R.S.
        • Luxwolda M.F.
        • Offringa P.J.
        • Boersma E.R.
        • Dijck-Brouwer D.A.
        • Muskiet F.A.
        Fetal intrauterine whole body linoleic, arachidonic and docosahexaenoic acid contents and accretion rates.
        Prostaglandins Leukot Essent Fatty Acids. 2012; 86: 13-20
        • Lien E.L.
        • Richard C.
        • Hoffman D.R.
        DHA and ARA addition to infant formula: current status and future research directions.
        Prostaglandins Leukot Essent Fatty Acids. 2018; 128: 26-40
        • Mun J.G.
        • Legette L.L.
        • Ikonte C.J.
        • Mitmesser S.H.
        Choline and DHA in maternal and infant nutrition: synergistic implications in brain and eye health.
        Nutrients. 2019; 11: 1125
        • Janssen C.I.
        • Zerbi V.
        • Mutsaers M.P.
        • de Jong B.S.
        • Wiesmann M.
        • Arnoldussen I.A.
        • et al.
        Impact of dietary n-3 polyunsaturated fatty acids on cognition, motor skills and hippocampal neurogenesis in developing C57BL/6J mice.
        J Nutr Biochem. 2015; 26: 24-35
        • Kodas E.
        • Galineau L.
        • Bodard S.
        • Vancassel S.
        • Guilloteau D.
        • Besnard J.C.
        • et al.
        Serotoninergic neurotransmission is affected by n-3 polyunsaturated fatty acids in the rat.
        J Neurochem. 2004; 89: 695-702
        • Tam E.W.
        • Chau V.
        • Barkovich A.J.
        • Ferriero D.M.
        • Miller S.P.
        • Rogers E.E.
        • et al.
        Early postnatal docosahexaenoic acid levels and improved preterm brain development.
        Pediatr Res. 2016; 79: 723-730
        • Cao D.
        • Kevala K.
        • Kim J.
        • Moon H.S.
        • Jun S.B.
        • Lovinger D.
        • et al.
        Docosahexaenoic acid promotes hippocampal neuronal development and synaptic function.
        J Neurochem. 2009; 111: 510-521
        • Moon K.
        • Rao S.C.
        • Schulzke S.M.
        • Patole S.K.
        • Simmer K.
        Longchain polyunsaturated fatty acid supplementation in preterm infants.
        Cochrane Database Syst Rev. 2016; 12: CD000375
        • Vohr B.R.
        • Wright L.L.
        • Dusick A.M.
        • Perritt R.
        • Poole W.K.
        • Tyson J.E.
        • et al.
        Center differences and outcomes of extremely low birth weight infants.
        Pediatrics. 2004; 113: 781-789
        • Molina T.L.
        • Stoll B.
        • Mohammad M.
        • Mohila C.A.
        • Call L.
        • Cui L.
        • et al.
        New generation lipid emulsions increase brain DHA and improve body composition, but not short-term neurodevelopment in parenterally-fed preterm piglets.
        Brain Behav Immun. 2019; 85: 46-56
        • Wang Q.
        • Cui Q.
        • Yan C.
        The effect of supplementation of long-chain polyunsaturated fatty acids during lactation on neurodevelopmental outcomes of preterm infant from infancy to school age: a systematic review and meta-analysis.
        Pediatr Neurol. 2016; 59: 54-61.e1
        • Clandinin M.T.
        • Chappell J.E.
        • Leong S.
        • Heim T.
        • Swyer P.R.
        • Chance G.W.
        Intrauterine fatty acid accretion rates in human brain: implications for fatty acid requirements.
        Early Hum Dev. 1980; 4: 121-129
        • Hadley K.B.
        • Ryan A.S.
        • Forsyth S.
        • Gautier S.
        • Salem Jr., N.
        The essentiality of arachidonic acid in infant development.
        Nutrients. 2016; 8: 216
        • Koletzko B.
        • Bergmann K.
        • Brenna J.T.
        • Calder P.C.
        • Campoy C.
        • Clandinin M.T.
        • et al.
        Should formula for infants provide arachidonic acid along with DHA? A position paper of the European Academy of Paediatrics and the Child Health Foundation.
        Am J Clin Nutr. 2020; 111: 10-16
        • Wainwright P.E.
        • Xing H.C.
        • Mutsaers L.
        • McCutcheon D.
        • Kyle D.
        Arachidonic acid offsets the effects on mouse brain and behavior of a diet with a low (n-6):(n-3) ratio and very high levels of docosahexaenoic acid.
        J Nutr. 1997; 127: 184-193
        • Calder P.C.
        Mechanisms of action of (n-3) fatty acids.
        J Nutr. 2012; 142: 592S-599S
        • Garg M.L.
        • Wierzbicki A.A.
        • Thomson A.B.
        • Clandinin M.T.
        Omega-3 fatty acids increase the arachidonic acid content of liver cholesterol ester and plasma triacylglycerol fractions in the rat.
        Biochem J. 1989; 261: 11-15
        • Makrides M.
        • Gibson R.A.
        • McPhee A.J.
        • Collins C.T.
        • Davis P.G.
        • Doyle L.W.
        • et al.
        Neurodevelopmental outcomes of preterm infants fed high-dose docosahexaenoic acid: a randomized controlled trial.
        JAMA. 2009; 301: 175-182
        • Fewtrell M.S.
        • Abbott R.A.
        • Kennedy K.
        • Singhal A.
        • Morley R.
        • Caine E.
        • et al.
        Randomized, double-blind trial of long-chain polyunsaturated fatty acid supplementation with fish oil and borage oil in preterm infants.
        J Pediatr. 2004; 144: 471-479
        • Meldrum S.J.
        • D'Vaz N.
        • Simmer K.
        • Dunstan J.A.
        • Hird K.
        • Prescott S.L.
        Effects of high-dose fish oil supplementation during early infancy on neurodevelopment and language: a randomised controlled trial.
        Br J Nutr. 2012; 108: 1443-1454
        • O'Connor D.L.
        • Hall R.
        • Adamkin D.
        • Auestad N.
        • Castillo M.
        • Connor W.E.
        • et al.
        Growth and development in preterm infants fed long-chain polyunsaturated fatty acids: a prospective, randomized controlled trial.
        Pediatrics. 2001; 108: 359-371
        • Westerberg A.C.
        • Schei R.
        • Henriksen C.
        • Smith L.
        • Veierod M.B.
        • Drevon C.A.
        • et al.
        Attention among very low birth weight infants following early supplementation with docosahexaenoic and arachidonic acid.
        Acta Paediatr. 2011; 100: 47-52
        • Linsell L.
        • Malouf R.
        • Morris J.
        • Kurinczuk J.J.
        • Marlow N.
        Prognostic factors for poor cognitive development in children born very preterm or with very low birth weight: a systematic review.
        JAMA Pediatr. 2015; 169: 1162-1172
        • Kapoor V.
        • Malviya M.N.
        • Soll R.
        Lipid emulsions for parenterally fed preterm infants.
        Cochrane Database Syst Rev. 2019; 6: CD013163