+ The Role of Nutrition in Fetal Alcohol Spectrum Disorders (FASD) Christina Chambers, PhD, MPH University of California San Diego International Conference on FASD – Krakow, Poland October 1, 2015 + Nutrition and FASD In Nutritional status may lead to a maternal-fetal environment in which the effect of prenatal alcohol is either amplified or reduced In alcohol-exposed pregnancies children with FASD Nutritional status may modify cognitive, behavior or growth abnormalities Keen CL et al, Biofactors, 2010 + What is the evidence that maternal nutrition is important in FASD? + Maternal iron deficiency exacerbates the effect of prenatal alcohol on conditioned responses in rat pups Rufer et al, PLOS One, 2012 + Prenatal choline supplementation reduces learning and growth deficits caused by prenatal alcohol in an rat model Thomas et al, Neurotox and Teratol, 2009 + Choline targets Choline supplementation may be targeting hippocampus which is important for learning and memory Choline may be targeting prefrontal cortex which is important for executive functioning (attention, working memory, behavioral flexibility and regulation) + Less adequate dietary intake in mothers of children with FASD in South Africa Nutrient Mothers FASD N=43 % <EAR Mothers No FASD N=85 % <EAR P-value Riboflavin 0.97 (0.31) 86% 1.16 (0.63) 62% 0.02 Calcium 305 (83) 100% 392 (187) 94% <0.001 Choline 239.4 (82.0) --- 271.1 (140.7) --- 0.05 DPA 0.006 (0.01) --- 0.014 (0.03) --- 0.02 May et al, Reproduc Toxicol, 2014 + What is the evidence that nutrition is important in children with FASD? + Postnatal supplementation ameliorates effects of prenatal alcohol in animal models Omega-3 supplements restore glutathione levels in the brain and prevent oxidative damage Vit D3 supplementation reduces perseverative behavior Choline supplementation dampens effects on spatial learning, working memory, reversal learning, and open field hyperactivity Patten et al, Neuroscience J Nutr Biochem, 2013 2013 Letters, Idrus et al, J Steroid Biochem Molec Biol, 2013 Thomas et al, various + Iron deficiency in infants exacerbates effects of alcohol dose on growth at 5 years of age Carter et al, Alc Clin Exper Res, 2012 + Vitamin supplements as an intervention for FASD in humans Examples of two trials recently completed that tested vitamin supplement interventions – one in pregnancy and one in children + Ukraine clinical study To assess the effectiveness of a vitamin/mineral supplement intervention in pregnancy on neurodevelopment of alcohol-exposed infants + Rivne Diagnostic Center team + Khmelnytsky Perinatal Center team Enrolled pregnant women who reported frequent binge drinking in pregnancy and pregnant women with no or low alcohol consumption Blood samples collected for nutrition measures Randomized women to a multivitamin/mineral supplement with or without additional 750 mg. choline “No intervention” arm received standard of care advice to take prenatal vitamins Bayley Scales of Infant Development II Information processing measured using cardiac orienting response (COR) habituation/dishabituation auditory or visual stimulus following an + Neurobehavioral testing + Information processing cardiac orienting response + Bayley Scales of Infant Development 163 in the alcohol exposed group evaluated at 6 months of age 204 in the low/unexposed group evaluated at 6 months of age + Psychomotor Developmental Index at 6 months of age Alcohol p <0.04; MVM – NS Coles et al, Matern Child Health J, 2015 + Mental Developmental Index at 6 months of age Alcohol dose p <0.001 Coles et al, Matern Child Health J, 2015 + Bayley Scales of Infant Development No additional benefit of choline supplementation + Information Processing COR 77 in the alcohol exposed group evaluated at 6-12 months of age 91 in the low/unexposed group evaluated at 6-12 months of age Kable et al, Alcohol 2015 in press + Information Processing COR Choline supplementation resulted in better performance in both alcohol exposed and unexposed infants Greater change in heart rate in visual habituation trials (p<0.001) Improved speed of response Kable et al, Alcohol 2015 in press + Information Processing COR Improvement in maternal choline blood level over the course of pregnancy was associated with better performance There was no evidence of a benefit of multivitamin mineral supplementation on this measure Kable et al, Alcohol 2015 in press Postnatal intervention trial Tanya Nguyen, PhD Postnatal choline supplement trial 55 children ages 5-10 years with confirmed histories of heavy prenatal alcohol exposure Randomized to receive choline supplements or placebo for a 6 week period Pre and post-test using a standard neurobehavioral testing battery, assessment of dietary intake 9 Delayed Matching to Sample 8 Number Correct Memory 7 6 5 4 3 2 1 Pattern Recognition Memory 0 20 Pre-test Paired Associates Learning 10 60 5 0 Pre-test Placebo: d = -.21 ■ Choline: d = .03 Post-test Total Errors (Adjusted) Number Correct 15 Post-test Placebo: d = .00 ■ Choline: d = -.14 50 40 30 20 10 0 Pre-test Post-test Placebo: d = -.25 ■ Choline: d = -.17 Spatial Span 4,5 4 Span Length Executive function 3,5 3 2,5 2 1,5 1 0,5 70 0 Spatial Working Memory Pre-test 50 40 45 30 Spatial Working Memory 40 20 35 10 0 Pre-test Placebo: d = -.25 ■ Choline: d = -.12 Post-test Strategy Score Total Errors 60 Post-test Placebo: d = .06 ■ Choline: d = -.07 30 25 20 15 10 5 0 Pre-test Post-test Placebo: d = -.16 ■ Choline: d = .36 Dietary choline Regardless of group, higher levels of dietary choline may be related to better memory performance at post-test, after controlling for pre-test performance Delayed Matching to Sample @ Post-test 16 Choline 14 Placebo 12 Number Correct 10 8 6 4 2 0 0 100 200 300 400 Daily Dietary Choline Intake (mg) 500 Considerations – both trials Duration, dose, timing of treatment (trimester? age of child?) Genetic susceptibility polymorphisms in PEMT, MTHFD1 and choline dehydrogenase may relate to higher dietary requirement for choline + Nutrition and growth in children with FASD: Growth deficiency or obesity? + Dietary intake in children with prenatal alcohol exposure/FASD 31 children with an FASD, 2.5-4.9 years of age Children with an FASD had significantly lower intakes of saturated fats, Vitamin D and calcium compared to NHANES Fugelstad et al, Neurotox and Teratol, 2013 + Dietary intake in children with prenatal alcohol exposure/FASD 19 children with prenatal alcohol exposure, mean age 9.6 years 50% of girls overweight/obese; 37% of boys had reduced stature, weight or BMI for age More than 50% had dietary intakes <RDA/AI for choline, Vitamin E, potassium, B-carotene, Vitamin D, and essential fatty acids Werts et al, Alc Clin Exper Res, 2014 + Overweight/obesity in children with FASD Increased rates of overweight or obesity seen in 445 children with FASD, particularly in adolescent females Fugelstad et al, Alc Clin Exp Res, 2014 + Follow-up of children in Ukraine Following children in the cohort to 5 years of age neurobehavior growth eating behavior nutrition + + Eating behaviors in 4 year old children Unexposed N = 50 Exposed N = 33 P-value Food Resp Enjoy Food Satiety 2.0 (0.6) 3.3 (0.7) 3.2 (0.6) 2.3 (0.5) 3.3 (0.7) 3.2 (0.5) 0.002 0.996 0.855 Slow Eating Emotional Eating Fussy Eating 2.6 (1.0) 3.0 (0.9) 0.052 2.3 (1.0) 2.8 (1.2) 0.100 3.0 (0.8) 2.9 (0.9) 0.627 + Eating behaviors in 4 year old females Food Resp Emotional Eating Unexposed N = 19 Exposed N = 15 P-value 1.8 (0.6) 2.1 (0.9) 2.6 (0.6) 3.1 (1.1) 0.002 0.008 + Eating behavior and growth Postnatal BMI Z scores collected at 2-5 time points from 1 month to 4 years of age Correlations between eating behaviors and growth trajectory compared within alcohol exposure groups + + + Summary Iron deficiency in mother and infant may exacerbate the effects of prenatal alcohol Multivitamin/mineral and choline supplements given during an alcoholexposed pregnancies were beneficial for infants on some measures of performance + Summary Choline supplements given over a 6 week period to school age children with FASD did not show benefit on neurobehavioral measures Dose, timing, duration, age of child, genetic susceptibility and dietary intake of choline may be important + Summary: eating behavior and growth Some evidence that children with FASD have altered dietary intakes Eating behavior up to 4 years of age is associated with BMI trajectory in alcoholexposed children Are children with FASD at increased risk for becoming overweight? If yes, is this mediated by altered eating behaviors? + Much more to be learned! + Thanks to collaborators and funders NIH-NIAAA and the Office of Dietary Supplements Lyuba Yevtushok, MD – Rivne Diagnostic Center Natalya Zymak, MD – Khmelnystky Perinatal Center Ken Jones, MD – UCSD Kerri Boutelle, PhD - UCSD Carl Keen, PhD – UC Davis Jan Uriu-Adams, PhD – UC Davis Claire Coles, PhD – Emory University Julie Kable, PhD – Emory University Wladimir Wertelecki, MD – University of South Alabama/UCSD Tanya Nguyen, PhD - SDSU + Thank you!