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

Wozniak, Jeffrey R.; Fuglestad, Anita J.; Eckerle, Judith K.; Fink, Birgit A.; Hoecker, Heather L.; Boys, Christopher J.; Radke, Joshua P.; Kroupina, Maria; Miller, Neely C.; Brearley, Ann M.; Zeisel, Steven H.; Georgieff, Michael

doi:10.3945/ajcn.114.099168

Cited by 96 publications

(105 citation statements)

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“…Thus, although choline's critical period is quite large, and effects can be seen in later developmental periods, supplementation earlier in development has greater benefits (5, 7). Wozniak et al (14) observed improved memory in children aged 2.5 to #4 y but not in children aged .4 to 5 y, which was consistent with both the timing and pattern that have been shown in preclinical studies. When we examined age strata as a factor, the data did not indicate a differential treatment response within any particular age group of children.…”

Section: Discussionsupporting

confidence: 59%

“…The null findings of this clinical trial were unanticipated because of the strong evidence that has suggested beneficial effects of choline supplementation in animal models of both typical development (39) and prenatal alcohol exposure (3)(4)(5)(6)(7)(8)10). However, this investigation was only one of a few trials to translate the aforementioned animal research to a human clinical trial of choline supplementation in FASDs, and previous studies, at earlier ages, have suggested some positive beneficial effects (13,14). Because of the early stage of this field of research, factors may have contributed to the divergent findings that were observed in this study compared with in other clinical studies and with the preclinical data.…”

Section: Discussionmentioning

confidence: 84%

“…The treatment duration of previous clinical studies was w9 mo (13,14). In preclinical studies, the period of choline administration ranged from 10 to 20 d, which is equivalent to years in human development.…”

Section: Discussionmentioning

confidence: 99%

“…Preclinical studies have primarily used choline salts (e.g., choline chloride or bitartrate) as did Wozniak et al (14). We chose glycerophosphocholine for several reasons as follows: 1) glycerophosphocholine is not converted to trimethylamine in the gut, which can impart a fishy body odor and, thereby, may reduce compliance; 2) the relative bioavailability of glycerophosphocholine is higher than that of phosphatidylcholine and choline salts and can more rapidly cross the blood-brain barrier (50,51); and 3) glycerophosphocholine has been shown to better augment the levels and release of brain acetylcholine, at least in dementia populations (52)(53)(54).…”

Section: Discussionmentioning

confidence: 99%

“…The first study was published as part of a larger clinical trial that explored micronutrient supplementation in alcohol-consuming pregnant women in the Ukraine (11,12) and showed that choline supplementation improved neurophysiologic encoding and memory in both alcohol-exposed and -unexposed infants (13). The second study was a randomized clinical trial of choline supplementation in preschool-aged children with FASDs and revealed that choline improved memory function in young children between the ages of 2.5 and 5 y (14). Therefore, given that previous clinical data suggest some cognitive benefits of choline supplementation in early developmental periods, we aimed to investigate the effectiveness of this intervention in older, school-aged children with FASDs.…”

Section: Introductionmentioning

confidence: 99%

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Randomized, double-blind, placebo-controlled clinical trial of choline supplementation in school-aged children with fetal alcohol spectrum disorders

Nguyen

Risbud

Mattson

et al. 2016

The American Journal of Clinical Nutrition

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Background: Prenatal alcohol exposure results in a broad range of cognitive and behavioral impairments. Because of the long-lasting problems that are associated with fetal alcohol spectrum disorders (FASDs), the development of effective treatment programs is critical. Preclinical animal studies have shown that choline, which is an essential nutrient, can attenuate the severity of alcohol-related cognitive impairments. Objective: We aimed to translate preclinical findings to a clinical population to investigate whether choline supplementation can ameliorate the severity of memory, executive function, and attention deficits in children with FASDs. Design: In the current study, which was a randomized, doubleblind, placebo-controlled clinical trial, we explored the effectiveness of a choline intervention for children with FASDs who were aged 5-10 y. Fifty-five children with confirmed histories of heavy prenatal alcohol exposure were randomly assigned to either the choline (n = 29) or placebo (n = 26) treatment arms. Participants in the choline group received 625 mg choline/d for 6 wk, whereas subjects in the placebo group received an equivalent dose of an inactive placebo treatment. Primary outcomes, including the performance on neuropsychological measures of memory, executive function, and attention and hyperactivity, were assessed at baseline and postintervention. Results: Compared with the placebo group, participants in the choline group did not differentially improve in cognitive performance in any domain. Treatment compliance and mean dietary choline intake were not predictive of treatment outcomes. Conclusions: Findings of the current study do not support that choline, administered at a dose of 625 mg/d for 6 wk, is an effective intervention for school-aged (5-10 y old) children with FASDs. This research provides important information about choline's therapeutic window. Combined with other studies of choline and nutritional interventions in this population, this study emphasizes a further need for the continued study of the role of nutritional status and supplementation in children with FASDs and the contributions of nutrition to neurocognition. This trial was registered at clinicaltrials.gov as NCT01911299.Am J Clin Nutr 2016;104:1683-92.

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Section: Discussionsupporting

confidence: 59%

Section: Discussionmentioning

confidence: 84%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Randomized, double-blind, placebo-controlled clinical trial of choline supplementation in school-aged children with fetal alcohol spectrum disorders

Nguyen

Risbud

Mattson

et al. 2016

The American Journal of Clinical Nutrition

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Differential neuroimaging indices in prefrontal white matter in prenatal alcohol‐associated ADHD versus idiopathic ADHD

O’Neill

O’Connor

Yee

et al. 2019

Birth Defects Research

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Background: Attention deficit-hyperactivity disorder (ADHD) is common in fetal alcohol spectrum disorders (FASD) but also in patients without prenatal alcohol exposure (PAE). Many patients diagnosed with idiopathic ADHD may actually have ADHD and covert PAE, a treatment-relevant distinction. Methods: We compared proton magnetic resonance spectroscopic imaging (MRSI; N = 44) and diffusion tensor imaging (DTI; N = 46) of the anterior corona radiata (ACR)-a key fiber tract in models of ADHD-at 1.5 T in children with ADHD with PAE (ADHD+PAE), children with ADHD without PAE (ADHD−PAE), children without ADHD with PAE (non-ADHD+PAE), and children with neither ADHD nor PAE (non-ADHD−PAE, i.e., typically developing controls). Levels of choline-compounds (Cho) were the main MRSI endpoint, given interest in dietary choline for FASD; the main DTI endpoint was fractional anisotropy (FA), as ACR FA may reflect ADHD-relevant executive control functions. Results: For ACR Cho, there was an ADHD-by-PAE interaction (p = 0.038) whereby ACR Cho was 26.7% lower in ADHD+PAE than in ADHD−PAE children (p < 0.0005), but there was no significant ACR Cho difference between non-ADHD+PAE and non-ADHD−PAE children. Voxelwise false-discovery rate (FDR)-corrected analysis of DTI revealed significantly (q ≤ 0.0101-0.05) lower FA in ACR for subjects with PAE (ADHD+PAE or non-ADHD+PAE) than for subjects without PAE (ADHD−PAE or non-ADHD−PAE). There was no significant effect of ADHD on FA. Thus, in overlapping samples, effects of PAE on Cho and FA were observed in the same white-matter tract. Conclusions: These findings point to tract focal, white-matter pathology possibly specific for ADHD+PAE subjects. Low Cho may derive from abnormal choline metabolism; low FA suggests suboptimal white-matter integrity in PAE. More advanced MRSI and DTI-and neurocognitive assessments-may better distinguish ADHD+PAE from ADHD−PAE, helping identify covert cases of FASD.

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Nutrition and Brain Development

Cusick

Barks

Georgieff

2021

Current Topics in Behavioral Neurosciences

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

Cited by 96 publications

References 50 publications

Randomized, double-blind, placebo-controlled clinical trial of choline supplementation in school-aged children with fetal alcohol spectrum disorders

Randomized, double-blind, placebo-controlled clinical trial of choline supplementation in school-aged children with fetal alcohol spectrum disorders

Differential neuroimaging indices in prefrontal white matter in prenatal alcohol‐associated ADHD versus idiopathic ADHD

Nutrition and Brain Development

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