Anita J. Fuglestad

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 cholines effect on EI suggests that potential sensitive periods should be considered in future work. This trial was registered at clinicaltrials.gov as NCT01149538.

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.

Iron Deficiency in International Adoptees from Eastern Europe

OBJECTIVE To assess iron deficiency (ID) in international adoptees after adoption. STUDY DESIGN Participants (n = 37) were adopted into the United States from Eastern Europe before they were 24 months of age. Baseline (within 1 month post-adoption) and follow-up (6 months post-adoption) assessments included routine post-adoption clinical evaluations, anthropometrics, dietary intakes, and iron measures (hemogram and serum analysis). RESULTS At adoption and follow-up, mean percent transferrin saturation and mean corpucuscular volume were low compared with the US population. Mean serum ferritin concentration became lower than the US population at follow-up, although the mean daily iron intake was more than the Recommended Dietary Allowance. Participants with Giardia lamblia at baseline had more compromised iron status at baseline and follow-up. Growth rate (change in z-score/months between assessments) was negatively correlated with change in serum ferritin concentrations between baseline and follow-up (r = -0.34; P < .05). CONCLUSIONS International adoptees had compromised iron status, with ID more prevalent in participants with G lamblia, a parasite that may interfere with iron absorption. The persistent ID at follow-up was likely caused by the erythropoietic demands of catch-up growth.

Executive functioning deficits in preschool children with Fetal Alcohol Spectrum Disorders

Executive function (EF) deficit is a hallmark of Fetal Alcohol Spectrum Disorders (FASD), but the vast majority of available evidence comes from school-age children and adolescents. Very little is known about EF during the critical developmental period prior to 6 years of age in FASD. We evaluated EF in 39 children with FASD (3.0–5.5 years) and a comparison group of 50 age-matched, nonexposed controls. Measures included the EF Scale for Early Childhood and a Delay of Gratification task. Compared to age-matched controls, preschool children with FASD had impairments on the EF Scale and showed more impulsivity on the Delay of Gratification task. To confirm the EF Scale finding, FASD group performance was compared to a separate normative dataset (N = 1,400). Those with FASD performed below normal (M = –0.57, SD = 0.92). Within the FASD group, IQ was correlated with the EF Scale (partial r = .60, p = .001) and Delay of Gratification (partial r = .58, p = .005). EF Scale performance did not differ significantly across levels of FASD severity (fetal alcohol syndrome [FAS], partial FAS, or alcohol-related neurobehavioral disorder [ARND]). However, compared to normative data, those with FAS had the largest deficits (M = –0.91 SD from the mean, SE = 0.23), followed by partial FAS (M = –0.66 SD from the mean, SE = 0.26), then ARND (M = –0.36 SD from the mean, SE = 0.20). These novel data show that EF deficits manifest well before the age of 6 years in children with FASD, that they occur across the spectrum, and that EF may be most impaired in children with more severe forms of FASD and/or lower IQs.

Beyond Stimulus Deprivation: Iron Deficiency and Cognitive Deficits in Postinstitutionalized Children

Children adopted from institutions have been studied as models of the impact of stimulus deprivation on cognitive development (Nelson, Bos, Gunnar, & Sonuga-Barke, 2011), but these children may also suffer from micronutrient deficiencies (Fuglestad et al., 2008). The contributions of iron deficiency (ID) and duration of deprivation on cognitive functioning in children adopted from institutions between 17 and 36 months of age were examined. ID was assessed in 55 children soon after adoption, and cognitive functioning was evaluated 11-14.6 months postadoption when the children averaged 37.4 months old (SD = 4.9). ID at adoption and longer duration of institutional care independently predicted lower IQ scores and executive function (EF) performance. IQ did not mediate the association between ID and EF.

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.

Adoption as an intervention for institutionally reared children: HPA functioning and developmental status.

Institutional care, particularly when experienced early in life, is associated with delays in social and emotional development that often persist years after adoption. It has been hypothesized that compromise of the hypothalamic-pituitary-adrenocortical (HPA) axis due to adverse condition in institutions is a mediator of later emotional and behavioral problems. The first goal of our project was to investigate whether improvements in the social and emotional environment are associated with changes in HPA axis function. The second goal was to explore whether HPA alterations related to early social adversity were associated with more compromised general development and social and emotional functioning post adoption. Children adopted from Eastern European orphanages (N = 76, mean age was 17 months, SD = 5) were followed as part of an ongoing longitudinal study. Data, including diurnal cortisol patterns, were collected at two time points: baseline (within one month of adoption) and follow-up (six months later). Cortisol values were averaged over two days of saliva sampling after wake-up and before bedtime. We found that morning cortisol values increased between the baseline assessment (M = 0.27 μg/dl, SD = 0.13) and follow-up (M = 0.33 μg/dl, SD = 0.20), t(76) = -2.1, p<0.05. HPA functioning was not associated with general developmental level at either the initial or six months post-adoption assessments. However, dysregulation of the HPA axis (i.e., flatter diurnal pattern) at follow-up was associated with more behavioral and emotional problems. Overall, these results suggest that investigating specific physiological mechanisms is important in identifying children at risk for persistent social and emotional problems and in understanding the long-term consequences of early adversity. Future work should investigate whether disturbance in the HPA system is a heightened risk for long-term negative developmental outcomes.

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.

Micronutrient status and neurodevelopment in internationally adopted children

To assess the status of nutrients relevant for brain development in internationally adoptees from disparate global regions and determine whether identified deficiencies are associated with neurodevelopment.

Maternal executive function, infant feeding responsiveness and infant growth during the first 3 months

There is limited research in young infants, particularly <3 months of age, on maternal feeding practices in spite of increasing evidence that early weight gain velocity is a determinant of later obesity risk.