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

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.

Overweight and obesity among children and adolescents with fetal alcohol spectrum disorders.

BACKGROUND: Because prenatal alcohol exposure is associated with growth deficiency, little attention has been paid to the potential for overweight and obesity in children with fetal alcohol spectrum disorders (FASD). This study examined the prevalence of overweight/obesity (body mass index [BMI]) in a large clinical sample of children with FASD. METHODS: Children, aged 2 to 19 years, who were evaluated for FASD at University Clinics, included 445 with an FASD diagnosis and 171 with No-FASD diagnosis. Prevalence of overweight/obesity (BMI ≥ 85 percentile) was compared to national and state prevalence. BMI was examined in relation to FASD diagnosis, gender, and age. Dietary intake data were examined for a young subsample (n = 42). RESULTS: Thirty-four percent with any FASD diagnosis were overweight or obese, which did not differ from the No-FASD group or U.S. prevalence. Underweight was prevalent in those with fetal alcohol syndrome (FAS) (17%). However, increased rates of overweight/obesity were seen in those with partial FAS (40%). Among adolescents, those with any FASD diagnosis had increased overweight/obesity (42%), particularly among females (50%). The rate in adolescent females with FASD (50%) was nearly 3 times higher than state prevalence for adolescent females (17 to 18%), p < 0.001. In the young subsample, those who were overweight/obese consumed more calories, protein, and total fat per day than those who were not overweight or obese. CONCLUSIONS: Rates of overweight/obesity are increased in children with partial FAS. In adolescents, rates are increased for any FASD diagnosis (particularly in females). Results are suggestive of possible metabolic/endocrine disruption in FASD-a hypothesis for which there is evidence from animal models. These data suggest that clinicians may consider prenatal alcohol exposure as a risk factor for metabolic/endocrine disruption, should evaluate diet as a risk in this population, and may need to target interventions to females prior to puberty to effect changes in overweight-related outcomes.

Choline supplementation in children with fetal alcohol spectrum disorders has high feasibility and tolerability.

There are no biological treatments for fetal alcohol spectrum disorders (FASDs), lifelong conditions associated with physical anomalies, brain damage, and neurocognitive abnormalities. In preclinical studies, choline partially ameliorates memory and learning deficits from prenatal alcohol exposure. This phase I pilot study evaluated the feasibility, tolerability, and potential adverse effects of choline supplementation in children with FASD. We hypothesized that choline would be well tolerated with minimal adverse events. The study design was a double-blind, randomized, placebo-controlled trial. Participants included 20 children aged 2.5 to 4.9 years with prenatal alcohol exposure and FASD diagnoses. Participants were randomly assigned to 500 mg choline or placebo daily for 9 months (10 active, 10 placebo). Primary outcome measures included feasibility, tolerability, adverse effects, and serum choline levels. Seventeen participants completed the study. Compliance was 82% to 87%, as evidenced by parent-completed log sheets and dose counts. Periodic 24-hour dietary recalls showed no evidence of dietary confounding. Adverse events were minimal and were equivalent in the active and placebo arms with the exception of fishy body odor, which occurred only in the active group. There were no serious adverse events to research participants. This phase I pilot study demonstrates that choline supplementation at 500 mg/d for 9 months in children aged 2 to 5 years is feasible and has high tolerability. Further examination of the efficacy of choline supplementation in FASD is currently underway.

Inadequate intake of nutrients essential for neurodevelopment in children with fetal alcohol spectrum disorders (FASD).

This study evaluated dietary intake in children with fetal alcohol spectrum disorders (FASD). Pre-clinical research suggests that nutrient supplementation may attenuate cognitive and behavioral deficits in FASD. Currently, the dietary adequacy of essential nutrients in children with FASD is unknown. Dietary data were collected as part of a randomized, double-blind controlled trial of choline supplementation in FASD. Participants included 31 children with FASD, ages 2.5-4.9 years at enrollment. Dietary intake data was collected three times during the nine-month study via interview-administered 24-hour recalls with the Automated Self-Administered 24-hour Recall. Dietary intake of macronutrients and 17 vitamins/minerals from food was averaged across three data collection points. Observed nutrient intakes were compared to national dietary intake data of children ages 2-5 years (What we Eat in America, NHANES 2007-2008) and to the Dietary Reference Intakes. Compared to the dietary intakes of children in the NHANES sample, children with FASD had lower intakes of saturated fat, vitamin D, and calcium. The majority (>50%) of children with FASD did not meet the Recommended Dietary Allowance (RDA) or Adequate Intake (AI) for fiber, n-3 fatty acids, vitamin D, vitamin E, vitamin K, choline, and calcium. This pattern of dietary intake in children with FASD suggests that there may be opportunities to benefit from nutritional intervention. Supplementation with several nutrients, including choline, vitamin D, and n-3 fatty acids, has been shown in animal models to attenuate the cognitive deficits of FASD. These results highlight the potential of nutritional clinical trials in FASD.

Global functional connectivity abnormalities in children with fetal alcohol spectrum disorders.

BACKGROUND: Previous studies, including those employing diffusion tensor imaging (DTI), have revealed significant disturbances in the white matter of individuals with fetal alcohol spectrum disorders (FASD). Both macrostructural and microstructural abnormalities have been observed across levels of FASD severity. Emerging evidence suggests that these white matter abnormalities are associated with functional deficits. This study used resting-state functional MRI (fMRI) to evaluate the status of network functional connectivity in children with FASD compared with control subjects. METHODS: Participants included 24 children with FASD, ages 10 to 17, and 31 matched controls. Neurocognitive tests were administered including Wechsler Intelligence Scales, California Verbal Learning Test (CVLT), and Behavior Rating Inventory of Executive Functioning. High-resolution anatomical MRI data and 6-minute resting-state fMRI data were collected. The resting-state fMRI data were subjected to a graph theory analysis, and 4 global measures of cortical network connectivity were computed: characteristic path length, mean clustering coefficient, local efficiency, and global efficiency. RESULTS: Results revealed significantly altered network connectivity in those with FASD. The characteristic path length was 3.1% higher (p = 0.04, Cohen's d = 0.47), and global efficiency was 1.9% lower (p = 0.04, d = 0.63) in children with FASD compared with controls, suggesting decreased network capacity that may have implications for integrative cognitive functioning. Global efficiency was significantly positively correlated with cortical thickness in frontal (r = 0.38, p = 0.005), temporal (r = 0.28, p = 0.043), and parietal (r = 0.36, p = 0.008) regions. No relationship between facial dysmorphology and functional connectivity was observed. Exploratory correlations suggested that global efficiency and characteristic path length are associated with capacity for immediate verbal memory on the CVLT (r = 0.41, p = 0.05 and r = 0.41, p = 0.01, respectively) among those with FASD. CONCLUSIONS: Resting-state functional connectivity measures provide new insight into the integrity of brain networks in clinical populations such as FASD. Results demonstrate that children with FASD have alterations in core components of network function and that these aspects of brain integrity are related to measures of structure and cognitive functioning.

Inter-hemispheric functional connectivity disruption in children with prenatal alcohol exposure.

BACKGROUND: MRI studies, including recent diffusion tensor imaging (DTI) studies, have shown corpus callosum abnormalities in children prenatally exposed to alcohol, especially in the posterior regions. These abnormalities appear across the range of fetal alcohol spectrum disorders (FASD). Several studies have demonstrated cognitive correlates of callosal abnormalities in FASD including deficits in visual-motor skill, verbal learning, and executive functioning. The goal of this study was to determine whether inter-hemispheric structural connectivity abnormalities in FASD are associated with disrupted inter-hemispheric functional connectivity and disrupted cognition. METHODS: Twenty-one children with FASD and 23 matched controls underwent a 6-minute resting-state functional MRI scan as well as anatomical imaging and DTI. Using a semi-automated method, we parsed the corpus callosum and delineated 7 inter-hemispheric white matter tracts with DTI tractography. Cortical regions of interest (ROIs) at the distal ends of these tracts were identified. Right-left correlations in resting fMRI signal were computed for these sets of ROIs, and group comparisons were made. Correlations with facial dysmorphology, cognition, and DTI measures were computed. RESULTS: A significant group difference in inter-hemispheric functional connectivity was seen in a posterior set of ROIs, the para-central region. Children with FASD had functional connectivity that was 12% lower than in controls in this region. Subgroup analyses were not possible owing to small sample size, but the data suggest that there were effects across the FASD spectrum. No significant association with facial dysmorphology was found. Para-central functional connectivity was significantly correlated with DTI mean diffusivity, a measure of microstructural integrity, in posterior callosal tracts in controls but not in FASD. Significant correlations were seen between these structural and functional measures, and Wechsler perceptual reasoning ability. CONCLUSIONS: Inter-hemispheric functional connectivity disturbances were observed in children with FASD relative to controls. The disruption was measured in medial parietal regions (para-central) that are connected by posterior callosal fiber projections. We have previously shown microstructural abnormalities in these same posterior callosal regions, and the current study suggests a possible relationship between the two. These measures have clinical relevance as they are associated with cognitive functioning.