Combined choline and DHA supplementation: a randomized controlled trial
- 31 Downloads
Choline and docosahexaenoic acid (DHA) are essential nutrients for preterm infant development. They are metabolically linked via phosphatidylcholine (PC), a constitutive plasma membrane lipid and the major transport form of DHA in plasma. Plasma choline and DHA-PC concentrations rapidly decline after preterm birth. To improve preterm infant nutrition, we evaluated combined compared to exclusive choline and DHA supplementation, and standard feeding.
Randomized partially blinded single-center trial.
Neonatal tertiary referral center in Tübingen, Germany.
24 inborn preterm infants < 32 week postmenstrual age.
Standard nutrition (control) or, additionally, enteral choline (30 mg/kg/day), DHA (60 mg/kg/day), or both for 10 days. Single enteral administration of 3.6 mg/kg [methyl-D9-] choline chloride as a tracer at 7.5 days.
Main outcome measures
Primary outcome variable was plasma choline following 7 days of supplementation. Deuterated and unlabeled choline metabolites, DHA-PC, and other PC species were secondary outcome variables.
Choline supplementation increased plasma choline to near-fetal concentrations [35.4 (32.8–41.7) µmol/L vs. 17.8 (16.1–22.4) µmol/L, p < 0.01] and decreased D9-choline enrichment of PC. Single DHA treatment decreased DHA in PC relative to total lipid [66 (60–68)% vs. 78 (74–80)%; p < 0.01], which was prevented by choline. DHA alone increased DHA-PC only by 35 (26–45)%, but combined treatment by 63 (49–74)% (p < 0.001). D9-choline enrichment showed preferential synthesis of PC containing linoleic acid. PC synthesis via phosphatidylethanolamine methylation resulted in preferential synthesis of DHA-containing D3-PC, which was increased by choline supplementation.
30 mg/kg/day additional choline supplementation increases plasma choline to near-fetal concentrations, dilutes the D9-choline tracer via increased precursor concentrations and improves DHA homeostasis in preterm infants.
clinicaltrials.gov. Identifier: NCT02509728.
KeywordsArachidonic acid Choline D9-choline Combined supplementation Docosahexaenoic acid Neonate Nutrition LC-PUFA PEMT Phosphatidylcholine Phospholipid Plasma Preterm infant Stable isotopes Tandem mass spectrometry
Arachidonic acid (C20:4)
Docosahexaenoic acid (C22:6)
Linoleic acid (C18:2)
Oleic acid (C18:1)
European Society of Paediatric Gastroenterology::Hepatology and Nutrition
Heated electrospray ionization interface
Liquid chromatography–electrospray ionization interface tandem mass spectrometry
Long-chain polyunsaturated fatty acid
Neonatal intensive care unit
Randomized controlled trial
Specific reaction monitoring
Very low-density lipoproteins
This study was supported by an institutional grant to Christoph Maas (project no. E.03.27032.1) of the University of Tübingen. The authors would like to thank Alisa Bernhard, Katharina Löhner-Böttcher, Anne-Sophie Meixner, Anita Spiegelberg and Emmanuelle Seyboldt-Allaire for their help in sample as well as clinical data collection, respectively.
ARF, CM, and WB conceptualized and designed this trial. CM obtained an institutional grant for this study, and was involved in sample collection, assessment of clinical data, manuscript revision, and approval as submitted. WB developed the analytical techniques, supervised the analyses, drafted the initial manuscript, and approved the final manuscript as submitted. AS prepared the samples, carried out the mass spectrometric, and gas chromatographic analyses. KB, CM, and ARF recruited patients, supervised the patients’ well-being, and collected the study samples. KB, MM, and JH collected and recorded clinical data, revised the manuscript and approved the final manuscript as submitted. VH prepared and controlled the choline supplement, and ES supervised the fatty acid analysis. CFP supervised the project as the head of department, critically reviewed the manuscript, and approved the final manuscript as submitted. ARF was coordinator of the project. He was responsible for concept and design of the randomized trial, contributed to patient recruitment and supervision and to sample collection and assessment of clinical data, revised the manuscript and approved the final manuscript as submitted.
This study was funded by an internal Grant of the Eberhard-Karls-University, Medical Faculty, Tübingen (E.03.27032.1).
Compliance with ethical standards
Axel Franz has received speaker or consultant honoraria from Nestlé, Milupa, and Hipp, all marketing infant formulas. Furthermore, Axel Franz has received grants from Nestlé for the conduct of educational seminars and for the conduct of a clinical study. Furthermore, Axel Franz and Wolfgang Bernhard have received consultant honoraria from Baxter and Fresenius Kabi, all marketing components of parenteral nutrition. All the other authors indicate they have no financial relationships relevant to this article.
Conflict of interest
Based on current and previous work of this group, the University of Tuebingen, Medical Faculty, submitted a patent application for the combined administration of choline, ARA and DHA for prevention of developmental disorders associated with very preterm birth. The inventors of said patent application (WB, ARF) and all the other authors indicate that they do not have any conflict of interest to disclose.
- 2.Calder PC, Dangour AD, Diekman C, Eilander A, Koletzko B, Meijer GW, Mozaffarian D, Niinikoski H, Osendarp SJ, Pietinen P, Schuit J, Uauy R (2010) Essential fats for future health. In: Proceedings of the 9th Unilever nutrition symposium, 26–27 May 2010. Eur J Clin Nutr (2010) 64(Suppl4):S1–S13Google Scholar
- 3.Institute of Medicine, Food and Nutrition Board (1998) Dietary reference intakes for thiamin, riboflavin, niacin, vitamin B6, folate, vitamin B12, pantothenic acid, biotin, and choline vol 1, Chap. 14. Natl. Acad. Press, Washington DC, pp 390–422Google Scholar
- 11.Stocker JT, Dehner LP, Husain AN (2001) Means and standard deviations of weights and measurements of lifeborn infants by body weight. In: Stocker JT, Dehner LP (eds) Stocker and Dehner’s pediatric pathology, appendix 28–29, 2nd edn. Lippincott Williams & Wilkins, Philadelphia, pp 1302–1304Google Scholar
- 13.Voigt M, Rochow N, Straube S, Briese V, Olbertz D, Jorch G (2010) Birth weight percentile charts based on daily measurements for very preterm male and female infants at the age of 154–223 days. J Perinat Med 2010 38:289–295Google Scholar
- 22.The AOCS Lipid Library (2013) Plasma lipoproteins—composition, structure and biochemistry. http://lipidlibrary.aocs.org/lipids/lipoprot/index.htm. Accessed 18 Aug 2018
- 27.Vanek VW, Borum P, Buchman A, Fessler TA, Howard L, Jeejeebhoy K, Kochevar M, Shenkin A, Valentine CJ; Novel Nutrient Task Force, Parenteral Multi-Vitamin and Multi–Trace Element Working Group; American Society for Parenteral and Enteral Nutrition (ASPEN) Board of Directors (2012) A.S.P.E.N. position paper: recommendations for changes in commercially available parenteral multivitamin and multi-trace element products. Nutr Clin Pract 27:440–91CrossRefGoogle Scholar
- 28.Buchman AL, Ament ME, Sohel M, Dubin M, Jenden DJ, Roch M, Pownall H, Farley W, Awal M, Ahn C (2001) Choline deficiency causes reversible hepatic abnormalities in patients receiving parenteral nutrition: proof of a human choline requirement: a placebo-controlled trial. J Parenter Enteral Nutr 25:260–268CrossRefGoogle Scholar
- 29.Agostoni C, Buonocore G, Carnielli VP, De Curtis M, Darmaun D, Decsi T, Domellöf M, Embleton ND, Fusch C, Genzel-Boroviczeny O, Goulet O, Kalhan SC, Kolacek S, Koletzko B, Lapillonne A, Mihatsch W, Moreno L, Neu J, Poindexter B, Puntis J, Putet G, Rigo J, Riskin A, Salle B, Sauer P, Shamir R, Szajewska H, Thureen P, Turck D, van Goudoever JB, Ziegler EE, ESPGHAN Committee on Nutrition (2010) Enteral nutrient supply for preterm infants: commentary from the European Society of Paediatric Gastroenterology, Hepatology and Nutrition Committee on Nutrition. J Pediatr Gastroenterol Nutr 50:85–91CrossRefGoogle Scholar
- 31.Collins CT, Makrides M, McPhee AJ, Sullivan TR, Davis PG, Thio M, Simmer K, Rajadurai VS, Travadi J, Berry MJ, Liley HG, Opie GF, Tan K, Lui K, Morris SA, Stack J, Stark MJ, Chua MC, Jayagobi PA, Holberton J, Bolisetty S, Callander IR, Harris DL, Gibson RA (2017) Docosahexaenoic acid and bronchopulmonary dysplasia in preterm infants. N Engl J Med 376:1245–1255CrossRefGoogle Scholar
- 40.Alshweki A, Muñuzuri AP, Baña AM, de Castro MJ, Andrade F, Aldamiz-Echevarría L, de Pipaón MS, Fraga JM, Couce ML (2015) Effects of different arachidonic acid supplementation on psychomotor development in very preterm infants; a randomized controlled trial. Nutr J 14:101. https://doi.org/10.1186/s12937-015-0091-3 CrossRefGoogle Scholar