Marie Caudill, PhD, RD Professor, Division of Nutritional Sciences Cornell University

1. Choline: exploring the growing science on its benefits for moms, during fetal development and beyond Marie Caudill, PhD, RD Professor, Division of Nutritional Sciences Cornell University July 16, 2019

2. Disclosures • Grants / Research Support • National Institute of Health, United States Department of Agriculture, Balchem Corporation, Egg Nutrition Center, National Cattlemen’s Beef Association / Beef Checkoff • Other Financial or Material Support / Honorarium • Balchem Corporation

3. Choline: Historical Tidbits 1998 1932 1990s Charles H. Best Steven H. Zeisel

4. What Does Choline Do? Phosphatidylcholine (PC) PC TAGs ApoB Membrane Biosynthesis VLDL Fat Export

5. What Does Choline Do? Acetylcholine Neurotransmission

6. What Does Choline Do? Methyl Donor Synthesis/Metabolism of Numerous Biomolecules: Creatine Phospholipids Hormones Neurotransmitters and DNA Methylation Lasting effects on gene expression

7. Choline Plays a Fundamental Role in Human Health Across the Life Cycle

8. Large Amounts of Choline are Required During Pregnancy • Learning • Memory • Attention Fetal Growth Brain Development Recognized as a “brain building” nutrient by the Am Acad of Pediatrics CH3 CH3 Lasting Effects on Health CH3 Gene Expression Cellular Function Fetal DNA Methylation

9. A Higher Maternal Choline Intake Improves Several Pregnancy Outcomes

10. Higher Maternal Choline Intake Reduces Risk of Neural Tube Defects Shaw GM, et al. Am J Epidemiol. 2004;160:102-109. Shaw GM, et al. Epidemiology. 2009;20:714-719.

11. Higher Maternal Choline Intake Eases Baby’s Response to Stress CRH Hypothalamus * mg/dL CRH ACTH Placenta Pituitary Infant Plasma Cortisol Cortisol Cortisol Adrenal Cortex Jiang X, et al. FASEB J. 2012;26:3563-3574. Circulation

12. Lower Production of Cortisol in “Choline Babies” May Reduce Risk of Stress-Related Diseases CRH • Hypertension • Obesity • Type 2 Diabetes • Depression Hypothalamus ACTH • Memory • Learning • Attention Pituitary “Choline” Baby Cortisol Adrenal Cortex

13. Placenta Higher Maternal Choline Intake Lowers Preeclampsia Risk Factor, sFLT1 - + + + + In PE, placenta produces too much sFLT1 Preeclampsia Maternal blood vessel sFLT1 Endothelial Cell VEGF VEGF VEGF VEGF FLT1 Impaired VEGF binding to mFLT1 Endothelial dysfunction mFLT1 Jiang X, et al. FASEB J. 2012;27:1245-1253. Maternal hypertension Maternal kidney impairment

14. Higher Maternal Choline Intake Lowers Preeclampsia Risk Factor, sFLT1 - - - - + In PE, placenta produces too much sFLT1 Choline Placenta VEGF VEGF sFLT1 VEGF Endothelial Cell VEGF FLT1 VEGF Normal VEGF binding to mFLT1 Maternal blood vessel mFLT1 Jiang X, et al. FASEB J. 2012;27:1245-1253. Endothelial health

15. Higher Maternal Choline Intake Improves Offspring Cognitive Functioning (rodents) CH3 CON = control; SUP = supplementation. Meck WH, Williams CL. Neurosci Biobehav Rev. 2003;27:385-399.

16. Higher Maternal Choline Intake Improves Infant Information Processing Speed (humans) Caudill et al. FASEB J. 2018;32:2172-2180 Administered a visual attention task to measure eye movement reaction time to sequences of briefly presented visual stimuli

17. Cognitive Assessment in these Children at Age 7 Reveal Lasting Benefits of the Higher Maternal Choline Intake • Attention • Visual Memory • Problem Solving Bahnfleth et al. Curr Dev Nutr2019,3 (Suppl 1). Bahnfleth et al. ASN 2018 Abstract Submission ID:  424013

18. A Higher Choline Intake May Improve DHA Bioavailability Choline plays a role in the export of DHA from liver Higher choline intake increases the amount of PC-DHA in RBCs, a biomarker of DHA status, in women of reproductive age Suggests giving additional choline across gestation may be a way to increase DHA supply to the fetus Total PC-Fatty Acids, % by Weight Circulating PC-DHA Women of Reproductive Age West AA, et al. Am J Clin Nutr. 2013;97:718-727.

19. Less than 10 Percent of U.S. Pregnant Women are Meeting the Choline AI • Choline AI is 450 mg/d • Average choline intake is ~300-350 mg/d • Most prenatal or multivitamins do not contain the recommended amount of choline • This will likely change as the American Medical Association recently recommended choline be a component of all prenatal vitamin supplements

20. Recommendation for Consumers / Clients Prenatal Vitamin

21. Under-Consumption of Choline is NotLimited to Pregnant Women

22. Most Americans Do Not Achieve Adequate Intake Targets for Choline 550 550 Recommended (AI) 425 450 Actual Intake 200 mg/day NHANES 2009-2014 Source: http://cholinecouncil.com/health_professional/

23. Choline and The Dietary Guidelines for Americans • The 2015–2020 Dietary Guidelines for Americans Advisory Committee (DGAC) identified four nutrients with an Adequate Intake (AI) - vitamin K, fiber, potassium, and choline – that are under-consumed by children and adults. • However, only fiber and potassium were called as nutrients of public health concern. • And almost all of the USDA Healthy U.S.-Style Eating patterns included in the 2015-2020 DGA lack adequate choline. https://health.gov/dietaryguidelines/2015-scientific-report/ https://health.gov/dietaryguidelines/2015/guidelines/appendix-3/

24. The lack of recognition of choline as a nutrient of public health concern matters because…. • Federal food and nutrition health policies and programs are based on the DGA. For example: • The Special Supplemental Nutrition Program for Women, Infants and Children (WIC) uses DGA to determine the contents of its food packages and nutrition education program. • The USDA's National School Lunch Program and School Breakfast Program, which feeds more than 30 million children each school day, are informed by the DGA. https://health.gov/dietaryguidelines/2015/guidelines/introduction/dietary-guidelines-for-americans/

25. The Choline Gap: Why? The best dietary sources of choline are animal source foods like eggs and meat With public health calls to shift eating patterns away from animal-based foods, a potential unintended consequence is a further lowering of choline intake Vegans, vegetarians and even mainstream eaters are at risk of not meeting choline intake targets and may need a choline supplement Pregnant and lactating women are particularly vulnerable due to a higher choline requirement

26. Boosting Dietary Choline Intake • Egg yolk, large: 147 mg • Ground beef, 3 oz. cooked: 85 mg • Pork tenderloin, 3 oz. cooked: 83 mg • Salmon, Atlantic, farmed, 3 oz. cooked: 77 mg • Chicken breast, boneless, skinless, 3 oz. cooked: 65 mg • Navy beans, ½ cup cooked, 60 mg • Soybeans, ¼ cup roasted: 55 mg • Broccoli, 1 cup cooked: 51 mg https://ndb.nal.usda.gov/ndb/nutrients/report?nutrient1=421&nutrient2=&nutrient3=&fg=&max=25&subset=0&offset=100&sort=c&totCount=4551&measureby=m

27. Finding Choline on Food Labels • The FDA has set the Reference Daily Intake (RDI) for choline at 550 mg. • Food labeling of choline content is voluntary. • Foods with at least 55 mg of choline per serving are considered a “good source” of the nutrient. • Helpful in educating consumers about choline, and aiding them in selecting foods that supply it. https://s3.amazonaws.com/public-inspection.federalregister.gov/2016-11867.pdf

28. Key Takeaways • Large amounts of choline are required for normal fetal and neonatal development. • Higher maternal choline intake will likely improve pregnancy outcomes and offspring health. • Most pregnant and lactating women need to increase dietary choline intake or consume a choline supplement to meet recommendations. • Encourage selection and intake of choline-rich foods. Pay particular attention to pregnant / lactating women and those following vegetarian / vegan diets. • Evaluate each individual for their usual dietary intake and fill in the gap with a choline supplement.

29. For More Information on the Benefits of Choline at All Ages and Stages of Life… Check out “Healthy Ways to Increase Choline Intake” to download educational resources and choline-focused meal plans – Healthy U.S.-Style, Mediterranean, Vegetarian & Pregnancy Chat with Tom Druke or Lindsay MacNab if you’re interested in signing up for Balchem’s quarterly e-newsletter, The Choline Connection, which highlights new research, resources and choline in-the-news Visit VitaCholine.com for more choline research, resources and information on where you can purchase choline

30. Thank you!Questions? Marie Caudill, PhD, RD mac379@cornell.edu