title: Choline supplementation in children with fetal alcohol spectrum disorders: a randomized, double-blind, placebo-controlled trial.
abstract: BACKGROUND
  Fetal alcohol spectrum disorders (FASDs) are conditions characterized by physical anomalies, neurodevelopmental abnormalities, and neurocognitive deficits, including intellectual, executive, and memory deficits. There are no specific biological treatments for FASDs, but rodent models have shown that prenatal or postnatal choline supplementation reduces cognitive and behavioral deficits. Potential mechanisms include phospholipid production for axonal growth and myelination, acetylcholine enhancement, and epigenetic effects.
  
  
  OBJECTIVE
  Our primary goal was to determine whether postnatal choline supplementation has the potential to improve neurocognitive functioning, particularly hippocampal-dependent memory, in children with FASDs.
  
  
  METHODS
  The study was a double-blind, randomized, placebo-controlled pilot trial in children (aged 2.5-5 y at enrollment) with FASDs (n = 60) who received 500 mg choline or a placebo daily for 9 mo. Outcome measures were Mullen Scales of Early Learning (primary) and the elicited imitation (EI) memory paradigm (secondary).
  
  
  RESULTS
  The administration proved feasible, and choline was well tolerated. Participants received a dose on 88% of enrolled days. The only adverse event linked to choline was a fishy body odor. Choline supplementation improved the secondary outcome (EI) only after immediate recall performance was controlled for, and the outcome was moderated by age. The treatment effect on EI items recalled was significant in the younger participants (2.5- to ≤4.0-y-olds); the young choline group showed an increase of 12-14 percentage points greater than that of the young placebo group on delayed recall measures during treatment. However, there was a marginal baseline difference in delayed item recall between the young choline and placebo groups as well as a potential ceiling effect for item recall, both of which likely contributed to the observed treatment effect. We also observed a trend toward a negative effect of choline supplementation on the immediate EI recall of ordered pairs; the young placebo group showed an increase of 8-17 percentage points greater than that of the choline group during treatment. There was an inverse relation between choline dose (in mg/kg) and memory improvement (P = 0.041); the data suggest that weight-adjusted doses may be a better alternative to a fixed dose in future studies. Limitations included trend-level baseline differences in performance, the post-hoc determination of age moderation, and potential ceiling effects for the memory measure.
  
  
  CONCLUSIONS
  This pilot study suggests that an additional evaluation of choline supplementation as an intervention for memory functioning in children with FASDs is warranted. The observed interaction between age and choline's effect on EI suggests that potential sensitive periods should be considered in future work. This trial was registered at clinicaltrials.gov as NCT01149538.
authors.affiliation: Department of Psychiatry, jwozniak@umn.edu.
authors.forename: Jeffrey R
authors.identifier: http://orcid.org/0000-0002-7132-8519
authors.initials: JR
authors.lastname: Wozniak
authors.affiliation: Department of Psychiatry.
authors.forename: Anita J
authors.initials: AJ
authors.lastname: Fuglestad
authors.affiliation: Department of Pediatrics, and.
authors.forename: Judith K
authors.initials: JK
authors.lastname: Eckerle
authors.affiliation: Department of Psychiatry.
authors.forename: Birgit A
authors.initials: BA
authors.lastname: Fink
authors.affiliation: School of Public Health, Emory University, Atlanta, GA;
authors.forename: Heather L
authors.identifier: http://orcid.org/0000-0003-4374-1653
authors.initials: HL
authors.lastname: Hoecker
authors.affiliation: Department of Pediatrics, and.
authors.forename: Christopher J
authors.identifier: http://orcid.org/0000-0001-7709-1113
authors.initials: CJ
authors.lastname: Boys
authors.affiliation: Fagron Inc., St. Paul, MN; and.
authors.forename: Joshua P
authors.initials: JP
authors.lastname: Radke
authors.affiliation: Department of Pediatrics, and.
authors.forename: Maria G
authors.initials: MG
authors.lastname: Kroupina
authors.affiliation: Department of Pediatrics, and.
authors.forename: Neely C
authors.initials: NC
authors.lastname: Miller
authors.affiliation: Biostatistical Design and Analysis Center, University of Minnesota Twin Cities, Minneapolis, MN;
authors.forename: Ann M
authors.initials: AM
authors.lastname: Brearley
authors.affiliation: University of North Carolina at Chapel Hill Nutrition Research Institute, Kannapolis, NC.
authors.forename: Steven H
authors.identifier: http://orcid.org/0000-0002-9282-161X
authors.initials: SH
authors.lastname: Zeisel
authors.affiliation: Department of Pediatrics, and.
authors.forename: Michael K
authors.identifier: http://orcid.org/0000-0003-0844-6907
authors.initials: MK
authors.lastname: Georgieff
mesh_terms: D002675:Child, Preschool; D005260:Female; D006801:Humans; D008297:Male; D001526:Behavioral Symptoms / Q000209:etiology / Q000517:prevention & control; D002794:Choline / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D019587:Dietary Supplements / Q000009:adverse effects; D004311:Double-Blind Method; D005240:Feasibility Studies; D063647:Fetal Alcohol Spectrum Disorders / Q000178:diet therapy / Q000503:physiopathology / Q000523:psychology; D057194:Intention to Treat Analysis; D007858:Learning; D008137:Longitudinal Studies; D008570:Memory, Short-Term; D019965:Neurocognitive Disorders / Q000209:etiology / Q000517:prevention & control; D018697:Nootropic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D009812:Odorants; D010349:Patient Compliance; D010352:Patient Dropouts; D010865:Pilot Projects
chemical_list: D002794:Choline; D018697:Nootropic Agents
keywords: children; fetal alcohol spectrum disorder; fetal alcohol syndrome; memory; randomized double-blind placebo-controlled trial