July 6, 2016

Choline Supplementation in Children with Fetal Alcohol Spectrum Disorders

Pilot study suggests early supplementation may improve memory
Alcohol has destructive effects on the developing hippocampus, and studies show that choline positively effects hippocampus growth. This pilot study connects the dots, providing evidence that choline may have a real benefit for children with cognitive deficits related to prenatal alcohol exposure.


Wozniak JR, Fuglestad AJ, Eckerle JK, et al. Choline supplementation in children with fetal alcohol spectrum disorders: a randomized, double-blind, placebo-controlled trial. Am J Clin Nutr. 2015; 102(5):1113-1125.

Study Objective

To determine if postnatal choline supplementation has the potential to improve neurocognitive functioning, particularly hippocampal-dependent memory in children with FASDs


Double-blind, randomized, placebo-controlled pilot study


This study included 60 children with fetal alcohol syndrome disorders (FASDs) who were 2.5 to 5 years of age at time of enrollment. Exclusion criteria included another developmental disorder, neurological disorder, traumatic brain injury, or other medical conditions affecting the brain. Psychiatric comorbidities common with FASDs such as ADHD or learning disorders were not excluded. Eighty-three percent of participants had confirmed prenatal alcohol exposure that was determined by a self-report from the biological mother or social service records. The other participants who had unconfirmed alcohol exposure had dysmorphic faces and cognitive deficits suggesting prenatal alcohol exposure.
Modified Institute of Medicine (IOM) criteria was applied to the growth, facial dysmorphology, and alcohol exposure data collected in the clinic. Of the participants, 17% met criteria for fetal alcohol syndrome (FAS), 40% met criteria for partial FAS (pFAS), and 40% met criteria for alcohol-related neurodevelopmental disorder.
The results of this study are significant because very few medical interventions have proven effective for FASD.
The Centers for Disease Control and Prevention central nervous system (CNS) criteria for FASD was applied to assess cognitive functioning. Thirty-two percent of the participants met criteria for FASD diagnosis on the basis of deficient brain development, 25% had global cognitive impairment, and 95% had deficits in 3 or more domains (ie, intellectual, language, motor, visual-perceptual, adaptive functioning, behavioral).

Study Parameters Assessed

The participants received 500 mg choline (1.25 g choline bitartrate) or a placebo daily for 9 months. The contents were supplied in foil packets that contained a powdered, fruit-flavored drink mix.

Outcome Measures

Primary outcome

The Mullen Scales of Early Learning was used to assess global cognitive functioning. This test assesses visual reception, fine motor, receptive language, and expressive language abilities.

Secondary outcome

Hippocampal-dependent function was assessed using the elicited imitation (EI) memory task. The EI measures memory ability with behavioral imitation of action sequencing, which requires the hippocampus.

Key Findings 

The initial analysis found no significant difference between the treatment and placebo groups in either of the outcome measures (Mullen Scales or EI). The data was reevaluated taking age into account, and the analysis revealed that EI improvement differed depending on the child’s age. Investigators then divided the sample into 2 groups based on the median age. The younger group consisted of participants aged 4 years or younger; the older group were >4 to 5 years. 
After controlling for immediate recall performance, analysis revealed that choline supplementation improved delayed recall measures, and age influenced the effect. The younger choline group showed an increase of 12 to 14 percentage points greater than that of the younger placebo group in delayed recall. There was a negative effect of choline supplementation on the immediate EI recall of ordered pairs—the young placebo group showed an increase of 8 to 17 percentage points greater than the young treatment group. The only adverse effect of choline supplementation was a fishy body odor. The odor is a result of choline’s conversion to trimethylamine by gut microbes; trimethylamine is further converted in the liver to trimethylamine N-oxide. Overall, the choline supplementation was well-tolerated.

Practice Implications 

The prevalence of fetal alcohol syndrome disorders (FASDs) in the United States is 2% to 5%, and FASDs are among the most common causes of mental retardation.1 Studies have shown that alcohol in utero has teratogenic effects on the hippocampus and prefrontal cortex, which are involved in learning, memory, and executive function.2
The results of this study are significant because very few medical interventions have proven effective for FASD. 
The observed effect of choline on hippocampal-dependent memory is consistent with existing research on choline’s impact on synaptogenesis and hippocampal growth when supplemented postnatally.3 The results of this study showed significant benefit of choline supplementation only for participants under age 4. This may be related to the developmental stages of the hippocampus in the youngest participants, although this is speculation. 
In addition to postnatal choline supplementation, maternal choline supplementation impacts brain development during the prenatal period. Choline can cross the placenta, and the concentration in amniotic fluid is 10-fold greater than the concentration in maternal blood.4 Thomas et al reported that prenatal choline supplementation mitigates the adverse effects of prenatal alcohol exposure on development in rats.5 Pregnant rats were exposed to 6.0 g/kg/day of ethanol during days 5 to 20 of gestation, which is equivalent to the third trimester in humans. In addition, the rats were treated with 250 mg/kg/day of choline chloride. The choline supplementation decreased the detrimental effects on birth weight, incisor emergence, and behavioral measures caused by ethanol exposure. The behavioral performance of the ethanol-exposed rats that were supplemented with choline did not differ from that of controls. This study concluded that maternal choline supplementation during pregnancy has the potential to reduce the symptoms of fetal alcohol exposure and should be considered as an intervention for women who drink alcohol during pregnancy. 
Another clinical application of choline is that it increases acetylcholine (ACh), which enhances cholinergic neurotransmission and improves memory. Napoli et al measured the release of ACh from hippocampi of rats that received choline supplementation prenatally.6 Insulin-like growth factor 2 (IGF-2) and its receptor (IGF2R) were monitored because they have been shown to be mediators of endogenous ACh release7 and prenatal choline supplementation increases expression of IFG-2.8 The rats in this study were divided into 3 groups: choline-supplemented, control, and choline-deficient. During days 11 to 17 of pregnancy, the control group received 7.9 mmol/kg/day of choline, the choline-supplemented group received 35.6 mmol/kg/day, and the choline-deficient group received no choline. Hippocampal tissue was examined postnatally at days 18, 24, 34, and 80. In this study, prenatal choline supplementation had a significant effect on ACh release evoked by IGF-2/depolarization. The levels of IGF-2 mRNA, IGF-2 protein, and IGF2R protein in the hippocampus increased in the choline-supplemented group. These results suggest that prenatal choline supplementation has a beneficial impact on the cholinergic system, which should improve memory because ACh is released from cholinergic neurons that project into the hippocampus and cerebral cortex.  
To summarize, evidence suggests that early intervention with choline supplementation for children with FASDs benefits hippocampal development and memory function. Smaller choline doses given several times over the course of the day may decrease the potential of the adverse reaction of fishy body odor. Additional studies are needed to establish the optimal dosage—one that balances the improved memory performance with the adverse effect of unpleasant body odor—as well as the optimal duration of treatment.


This review is limited by the lack of recent research on choline supplementation in children. In addition, most studies available have been animal studies.

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  1. May PA, Gossage JP, Kalberg WO, et al. Prevalence and epidemiologic characteristics of FASD from various research methods with an emphasis on recent in-school studies. Dev Disabil Res Rev. 2009;15(3):176-192.
  2. Otero N, Thomas J, Saski C, Xia X, Kelly S. Choline Supplementation and DNA methylation in the hippocampus and prefrontal cortex of rats exposed to alcohol during development. Alcohol Clin Exp Res. 2012; 36(10): 1701-1709. 
  3. Zeisel SH. The fetal origins of memory: the role of dietary choline in optimal brain development. J Ped. 2006; 149(5 Suppl):131-136.
  4. Zeisel SH, Niculescu MD. Nutr Rev. 2006;64(4):197-203.
  5. Thomas JD, Abou EJ, Dominguez HD. Prenatal choline supplementation mitigates the adverse effects of prenatal alcohol exposure on development in rats. Neurotoxicol Teratol. 2009;31(5): 303-311.
  6. Napoli I, Blusztajn JK, Mellot TJ. Prenatal choline supplementation in rats increases the expression of IGF2 and its receptor IGF2R and enhances IGF2-induced acetylcholine release in hippocampus and frontal cortex. Brain Res. 2008;1237:124-135. 
  7. Hawkes C, Jhamandas JH, Harris KH, Fu W, MacDonald RG, Kar S. Single transmembrane domain insulin-like growth factor-II/mannose-6-phosphate receptor regulates central cholinergic function by activating a G-protein-sensitive, protein kinase C-dependent pathway. J Neurosci. 2006;26(2):585-596.
  8. Mellot TJ, Follettie MT, Diesl V, Hill AA, Lopez-Coviella I, Blusztajn JK. Prenatal choline availability modulates hippocampal and cerebral cortical gene expression. FASEB J. 2007;21(7):1311-1323.