Four-year follow-up of a randomized controlled trial of choline for neurodevelopment in fetal alcohol spectrum disorder

Abstract

Background: Despite the high prevalence of fetal alcohol spectrum disorder (FASD), there are few interventions targeting its core neurocognitive and behavioral deficits. FASD is often conceptualized as static and permanent, but interventions that capitalize on brain plasticity and critical developmental windows are emerging. We present a long-term follow-up study evaluating the neurodevelopmental effects of choline supplementation in children with FASD 4 years after an initial efficacy trial. Methods: The initial study was a randomized, double-blind, placebo-controlled trial of choline vs. placebo in 2-5year-olds with FASD. Participants include 31 children (16 placebo; 15 choline) seen 4 years after trial completion. The mean age at follow-up was 8.6 years. Diagnoses were 12.9% fetal alcohol syndrome (FAS), 41.9% partial FAS, and 45.1% alcohol-related neurodevelopmental disorder. The follow-up included measures of intelligence, memory, executive functioning, and behavior. Results: Children who received choline had higher non-verbal intelligence, higher visual-spatial skill, higher working memory ability, better verbal memory, and fewer behavioral symptoms of attention deficit hyperactivity disorder than the placebo group. No differences were seen for verbal intelligence, visual memory, or other executive functions. Conclusions: These data support choline as a potential neurodevelopmental intervention for FASD and highlight the need for long-term follow-up to capture treatment effects on neurodevelopmental trajectories.

Epigenetic Impacts of Early Life Stress in Fetal Alcohol Spectrum Disorders Shape the Neurodevelopmental Continuum

“…However, choline-supplemented infants have improved weight and head circumference at 6.5 and 12 months, in addition to better visual recognition memory compared to placebo infants (Jacobson et al, 2018 ). In a trial of choline administration in 2.5- to 5-year-olds with FASD, children who receive 500 mg of choline daily for 9 months have higher non-verbal intelligence, visual-spatial skills, working memory, verbal memory, and fewer symptoms associated with ADHD than the placebo group when assessed 4 years later (Wozniak et al, 2020 ). While the methyl-donor supplementation hypothesis has gained support, the precise mechanism of action is still unknown.…”

Examination of cortically projecting cholinergic neurons following exercise and environmental intervention in a rodent model of fetal alcohol spectrum disorders

“…Preclinical rodent studies indicate that choline supplementation concurrent with early postnatal AE or in adolescence reverses damage to the global epigenome of the hippocampus and PFC in addition to ameliorating cognitive and behavioral deficits in AE rats (Balaraman, Idrus, & Thomas, 2017;Bottom, Abbott, & Huffman, 2020;Davis, Tang, He, Lee, & Bearer, 2020;Otero, Thomas, Saski, Xia, & Kelly, 2012;Perkins, Fadel, & Kelly, 2015;Ryan, Williams, & Thomas, 2008;Schneider & Thomas, 2016). Clinical studies assessing the efficacy of maternal choline supplementation during the perinatal period demonstrate a transient increase in infant cognition speed and an increase in visual recognition memory in FASD-diagnosed infants (Caudill, Strupp, Muscalu, Nevins, & Canfield, 2018;Fuglestad et al, 2013Fuglestad et al, , 2015Jacobson et al, 2018;Wozniak et al, 2020). However, this outcome is inconsistent and is most efficacious when administered either during prenatal AE or prior to 5 years of age (Nguyen, Risbud, Mattson, Chambers, & Thomas, 2016).…”

Multifactorial Genetic and Environmental Hedgehog Pathway Disruption Sensitizes Embryos to Alcohol‐Induced Craniofacial Defects

“…Co‐environmental interactions have been observed between alcohol and dietary factors like iron deficiency (Helfrich et al, 2018; Huebner et al, 2016; Huebner et al, 2015; Rufer et al, 2012), which exacerbates alcohol teratogenicity, and choline or folate, which can reduce ethanol‐induced deficits (Bottom, Abbott and Huffman, 2020; Muralidharan, Sarmah and Marrs, 2015; Serrano et al, 2010; Shi et al, 2014; Thomas et al, 2010; Thomas and Tran, 2012). Choline supplementation in children has also been shown to be capable of partially ameliorating FASD‐associated neurocognitive deficits postnatally (Wozniak et al, 2020). In addition, either too much or too little retinoic acid can disrupt Hh signaling (Power, Lancman and Smith, 1999; Wang et al, 2019).…”