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

Sissel J Moltu; Tone Nordvik; Madelaine E Rossholt; Kristina Wendel; Maninder Chawla; Andres Server; Gunnthorunn Gunnarsdottir; Are Hugo Pripp; Magnus Domellöf; Marianne Bratlie; Marlen Aas; Petra S Hüppi; Alexandre Lapillonne; Mona K Beyer; Tom Stiris; Ivan I Maximov; Oliver Geier; Helle Pfeiffer

doi:10.1016/j.clnu.2023.11.037

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

Clin Nutr. 2024 Jan;43(1):176-186. doi: 10.1016/j.clnu.2023.11.037. Epub 2023 Nov 29.

Authors

Sissel J Moltu¹, Tone Nordvik², Madelaine E Rossholt³, Kristina Wendel², Maninder Chawla⁴, Andres Server⁴, Gunnthorunn Gunnarsdottir⁵, Are Hugo Pripp⁶, Magnus Domellöf⁷, Marianne Bratlie³, Marlen Aas², Petra S Hüppi⁸, Alexandre Lapillonne⁹, Mona K Beyer¹⁰, Tom Stiris¹¹, Ivan I Maximov¹², Oliver Geier¹³, Helle Pfeiffer¹⁴

Affiliations

¹ Department of Neonatal Intensive Care, Oslo University Hospital, 0424 Oslo, Norway. Electronic address: uxsilt@ous-hf.no.
² Department of Neonatal Intensive Care, Oslo University Hospital, 0424 Oslo, Norway.
³ Department of Pediatrics and Adolescence Medicine, Oslo University Hospital, 0424 Oslo, Norway.
⁴ Division of Radiology and Nuclear Medicine, Oslo University Hospital, 0424 Oslo, Norway.
⁵ Department of Pediatric Neurology, Oslo University Hospital, 0424 Oslo, Norway.
⁶ Oslo Centre of Biostatistics and Epidemiology, Oslo University Hospital, 0424 Oslo, Norway.
⁷ Department of Clinical Sciences, Pediatrics, Umeå University, 90185 Umeå, Sweden.
⁸ Department of Woman, Child and Adolescent Medicine, University of Geneva, 1211 Geneva, Switzerland.
⁹ Department of Neonatal Intensive Care, APHP Necker-Enfants Malades Hospital, Paris University, 75015 Paris, France.
¹⁰ Division of Radiology and Nuclear Medicine, Oslo University Hospital, 0424 Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
¹¹ Department of Neonatal Intensive Care, Oslo University Hospital, 0424 Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
¹² Department of Health and Functioning, Western Norway University of Applied Sciences, Bergen, Norway.
¹³ Department of Physics and Computational Radiology, Division of Radiology and Nuclear Medicine, Oslo University Hospital, Oslo, Norwary.
¹⁴ Department of Neonatal Intensive Care, Oslo University Hospital, 0424 Oslo, Norway; Department of Pediatric Neurology, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark.

PMID: 38061271
DOI: 10.1016/j.clnu.2023.11.037

Abstract

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.

Keywords: Arachidonic acid; Brain; Docosahexaenoic acid; Fatty acid supplementation; Neurodevelopment; Preterm.

Publication types

Randomized Controlled Trial
Research Support, Non-U.S. Gov't

MeSH terms

Arachidonic Acid
Brain / diagnostic imaging
Dietary Supplements
Diffusion Tensor Imaging / methods
Docosahexaenoic Acids
Female
Humans
Infant
Infant, Newborn
Infant, Premature*
Placenta
Pregnancy
White Matter* / diagnostic imaging

Substances

Docosahexaenoic Acids
Arachidonic Acid

Associated data

ClinicalTrials.gov/NCT03555019