Choline supplementation in children with fetal alcohol spectrum disorders: a randomized, double-blind, placebo-controlled trial12

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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.

Design: 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.

Keywords:

children
fetal alcohol spectrum disorder
fetal alcohol syndrome
memory
randomized double-blind placebo-controlled trial

ABBREVIATIONS

CNS
central nervous system
EI
elicited imitation
FAS
fetal alcohol syndrome
FASD
fetal alcohol spectrum disorder
IOM
Institute of Medicine
pFAS
partial fetal alcohol syndrome
REML
restricted maximum likelihood estimation
TMAO
trimethylamine N-oxide

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1

Supported by NIH grants 5R21AA019580 and R33AA019580 and in part by NIH grant P30DK056350 (to the University of North Carolina at Chapel Hill Nutrition Obesity Research Center).

2

Supplemental Table 1 and Supplemental Equations 1–7 are available from the “Online Supporting Material” link in the online posting of the article and from the same link in the online table of contents at http://ajcn.nutrition.org.