Maternal Choline and Infant

Cognition

Greta Mellinger
Penn State Dietetic Intern
Objectives
1. Recognize the multiple forms of choline in the body and their impact on
maternal, fetal, and infant health.

2. Interpret and critique current scientific findings related to increased choline

needs during pregnancy.

3. Apply scientific evidence for suggesting choline supplement/food

recommendations in clinical practice.
 Choline Timeline

1998
Declared an essential
1850 nutrient by the Institute
Theodore Gobley of Medicine.

1934 1991
Charles Best & Steven H. Zeisel
Frederick Banting

-Zeisel, S.H. (2012). A brief history of choline. Annals of nutrition & metabolism, 61(3), 254-8.
-Buchman, A. L., Ament, M. E., Sohel, M., Dubin, M., & al, e. (2001). Choline deficiency causes reversible hepatic abnormalities in patients receiving parenteral nutrition: Proof of a human
choline requirement: A placebo-controlled trial. JPEN, Journal of Parenteral and Enteral Nutrition, 25(5), 260-8. Retrieved from
http://ezaccess.libraries.psu.edu/login?url=https://search-proquest-com.ezaccess.libraries.psu.edu/docview/230240387?accountid=13158
 Choline Adequate Intake (AI)
- The AI for women was determined on a dose dependant alanine aminotransferase abnormalities in men.

○ AI Men 550 mg/day

○ AI Women 425 mg/day
○ AI Pregnant Women 450mg/day
○ AI Lactating Women 550 mg/day

- In a food frequency questionnaire daily choline intake was 300 mg/day (men n = 920; women n=1040).
1. Food and Nutrition Board, Institute of Medicine. Dietary Reference Intakes: Thiamin, Riboflavin, Niacin, Vitamin B-6, Vitamin B012, Pantothenic Acid, Biotin, and Choline. Washington,
D.C.: National Academy of Sciences; 1998. pp. 390–422.
2. Cho E, Zeisel SH, Jacques P, Selhub J, Dougherty L, Colditz GA, Willett WC. Dietary choline and betaine assessed by food-frequency questionnaire in relation to plasma total
homocysteine concentration in the Framingham Offspring Study. Am J Clin Nutr 2006;83(4):905–11.
 Choline in Food

USDA. http://www.ars.usda.gov/SP2UserFiles/Place/12354500/Data/Choline/Choln02.pdf.
 Choline
Functions
- Phosphorylated to
phosphatidylcholine

- Oxidized to betaine
for methylation

- Acetylated to
acetylcholine

Caudill, Marie A. Pre- and Postnatal Health: Evidence of Increased Choline Needs. J Am Diet Assoc. 2010 Aug;110(8):1198-206. doi: 10.1016/j.jada.2010.05.009.
 Clinical Applications through the Lifecycle
Neural tube Defect Non-alcoholic Fatty Alzheimer’s Disease
Shaw G.M., et al. Am J Epidemiol
2004;160:102–9 Liver Disease - Cholinergic
Zeisel, S.H. et al. Current opinion in
gastroenterology, 2012; 28(2), 159-65.
hypothesis of Alzheimer’s
- Folate mediated Disease
one-carbon metabolism - PC is needed for VLDL
uses methyl groups biosynthesis and export
from choline. into circulation - Cholinesterase
- inhibitors slow
- Could choline the action of
deficiency mask a folate acetylcholinesterase
deficiency?

Infant Cognition…..
 Choline Metabolism
De novo
biosynthesis

Methyl groups →
epigenetic
modification, one
carbon
metabolism,
Diet nucleotides

Caudill, Marie A. Pre- and Postnatal Health: Evidence of Increased Choline Needs. J Am Diet Assoc. 2010 Aug;110(8):1198-206. doi: 10.1016/j.jada.2010.05.009.
Increased Needs? “Pregnancy Alters Choline Dynamics”
Yan, J. et al. Pregnancy alters choline dynamics: results of a randomized trial using stable isotope methodology in pregnant and nonpregnant women, The American
Journal of Clinical Nutrition, Volume 98, Issue 6, 1 December 2013, Pages 1459–1467

-Tracer study on choline

partitioning during third
trimester.

-A 12 week feeding study

where choline was labeled
with deuterium in pregnant
versus non-pregnant women.

- Pregnant women use more choline to make PC via CDP-choline and PEMT pathways
- Higher use of betaine derived from choline as a methyl donor
- Higher catabolism of PC to free choline
- Conclusion: pregnancy has metabolic demands for choline
 Animal Studies: Choline and Cognitive Development
Research Question: What are the effects of prenatal
choline availability on memory function over time?

Methods: Cross-sectional animal model study design.

The rats were fed diets of prenatal choline
supplementation (SUP), normal diet(CON), or
deficient in choline (DEF). Placed in a maze.

Results: The SUP group made fewer episodic memory

errors.

Conclusions: Prenatal choline supplementation could

improve spatial memory function across the lifespan

Limitations: Animal study. How applicable is this to

humans?

Meck WH, Williams CL.Metabolic imprinting of choline by its availability during gestation: implications for memory and attentional processing across the lifespan. Neurosci Biobehav Rev. 2003
Sep;27(4):385-99.
 #1 RCT
Research question:

How does choline

supplementation
during the third
trimester of pregnancy
impact infant
cognition?

Caudill, M. A., Strupp, B. J., Muscalu, L., Nevins, J. E. H., Canfield, R. L. Maternal choline supplementation during the third trimester of pregnancy improves infant information processing speed:
a randomized, double-blind, controlled feeding study. FASEB J. 2018 Apr;32(4):2172-2180. doi: 10.1096/fj.201700692RR. Epub 2018 Jan 5.
#1 RCT
Method:

- A single-center, double blind, controlled

feeding study.

- Pre-screened women placed into two

groups (930 mg choline & 480 mg
choline).

- Infant information processing speed

tested at 4, 7, and 13 months.

- Included an adjusted analysis for

independent variables that were unknown
at participant selection.
#1 RCT
Results:

Infant mean saccade reaction

time as a function of age.

Enhanced reaction time, and

enhanced information
processing speed.
#1 RCT
Conclusions:

Supplementing the diet above the AI during the third trimester improved infant
information processing speed as compared to consumption at the AI.

Limitations:

- Small sample size (n=26).

- Used one model to address the effect of maternal supplementation on infant
cognition.
- Supplementation was only administered during the final trimester.
- Further longitudinal data beyond infancy.
#2 RCT
Research question:

Effects of perinatal choline on the

development of cerebral inhibition in
infants.

Schizophrenia:

Deficient cerebral inhibition and

sensory gating is characteristic of
schizophrenia.

CHRNA7 genotype is associated with

schizophrenia
Ross, R. G., Hunter, S. K., McCarthy, L., Beuler, J., Hutchison, A. K., Wagner, B. D., … Freedman, R. (2013).
Perinatal choline effects on neonatal pathophysiology related to later schizophrenia risk. The American Journal of
Psychiatry, 170(3), 290–298.
https://ajp-psychiatryonline-org.proxy.library.cornell.edu/doi/pdfplus/10.1176/appi.ajp.2012.12070940
#2 RCT
Methods:

Population: 100 healthy women were screened and entered the study at 2nd-trimester.
They completed a 7 day placebo lead-in and those that were 70% compliant were
randomly assigned to placebo or PC ~ 900 mg supplement. Dietary advice was provided to
the women on choline containing foods. PC supplementation in the infant continued for 3
months post birth. Electrophysiological recordings were obtained from 93 infants. 63
infants had the CHRNA7 genotype.

Dependant variable: the inhibition of the P50 ratio determined by a paired auditory
stimuli. A smaller ratio will indicate an inhibition.
#2 RCT
Results:
Panel A: The diminished amplitude
of the second response relative to the
first demonstrates cerebral inhibition,
quantified as the P50 ratio, which was
0.38 in the choline-treated infant and
0.92 in the placebo-treated infant

Panel B: A histogram of the P50 ratio at a mean adjusted age of

33 days. The dashed line demarcates the normal level of P50
inhibition, ratio 0.5. More choline than placebo-treated infants
were in this normal range
#2 RCT
Results Continued:

The CHRNA7 genotype diminished p50

inhibition (higher ratio) in the placebo
group, but not in the choline treated group.
#2 RCT
Conclusion: Infant development delay in neural inhibition activity is linked to attention
problems as a child matures. Choline supplementation encourages neural development of
cerebral inhibition.

Limitations:

- The first RCT done with maternal choline supplementation.

- Women had a depressive disorder and results may not be applicable to general
population.
- No measurement for the effect of choline on development of later mental illness.
- No control for diet outside of PC supplementation, except for dietary advice provided
by nursing 3 times during the study.
 #3 RCT

Research question: Will

supplementing pregnant and lactating
women with PC in addition to normal
dietary intake of choline enhance
cognition in infants?

Carol L Cheatham, Barbara Davis Goldman, Leslie M Fischer, Kerry-Ann da Costa, J

Steven Reznick, Steven H Zeisel; Phosphatidylcholine supplementation in pregnant
women consuming moderate-choline diets does not enhance infant cognitive function: a
randomized, double-blind, placebo-controlled trial, The American Journal of Clinical
Nutrition, Volume 96, Issue 6, 1 December 2012, Pages 1465–1472,
https://doi-org.proxy.library.cornell.edu/10.3945/ajcn.112.037184
#3 RCT
Methods:

Participants: 99 women completed the

placebo or supplement group (750 mg
PC) for 18 weeks of gestation and 90
days postpartum.

Diet: Women were told to keep a 3 day

food record at 30 weeks of gestation and
45 postpartum.

Dependant variable: multiple infant

cognition tests were completed at 10 and
12 months.
#3 RCT
Results:

There was no
significant findings
between the groups.
#3 RCT
Conclusion: When mothers consume 65-80% of the AI for choline, there is no advantage
for supplementing mothers with additional PC.

Limitations:
- Self-reported 3 day food recall
- The trial was double blind, but for ethical reasons the researchers had to inform the
women that the goal of the trial was to increase their choline levels.
 A Retrospective Case Control Study
Research Question:

Does higher maternal

intake of choline and
choline derived
metabolites associated
with increased memory
test scores in children
at age 7 years.

Caroline E. Boeke, Matthew W. Gillman, Michael D. Hughes, Sheryl L. Rifas-Shiman, Eduardo Villamor, and Emily Oken. Choline Intake During Pregnancy and Child Cognition at Age 7 Years.
American Journal of Epidemiology. Vol. 177, No. 12. doi: 10.1093/aje/kws395
 A Retrospective Case Control Study
Methods:
Results:
-Project Viva that was initiated in
1999 in MA, USA. 861
mother-child pairs in first trimester
and 808 chother-child pairs in
second trimester.

-A food frequency questionnaire

was used to determine dietary
choline intake.

-Cognitive tests (WRAML2) were

administered to children remaining
in the study at 7 years old.
- Choline intake was generally below the AI.
- A difference in the second trimester was seen in Q4, but not in the first
trimester.
- Other methyl donors (B12, Betaine, Folate) did not offer cognitive
enhancement.
A Retrospective Case Control Study
Conclusion: Higher maternal intake of choline, but not other methyl donors, was
associated with a moderately improved child memory at age 7.

Limitations:

- Dietary intake is difficult to measure in epidemiologic studies.

- The study visits were not all at the end of each women’s wither first or second trimester.
- Applying quartiles for nutrient intake could have introduced impercision.
- The cognitive exams were administered by a variety of trained research assistance. This variability among
research assistance, could have added variability in results because of its impact on the dependant variable,
infant cognition.
- Lack of follow-up data in the Project Viva, resulted in half of the original cohort (n= 1896) to be lost
Gaps in Research
1. No meta analysis for choline and infant cognition.

2. No randomized control trials that control for variable dietary intake across the entire
pregnancy.
a. Supplement study vs controlled feeding study

3. Lacking evidence for AI recommendations in pregnant

women.
Directions for Future Research
Should the AI for pregnant women be higher
than 450 mg?

- Additional RCT that control for a variable

dietary intake of choline in the first, second
and third trimester.

- Further epidemiologic studies combining multiple populations and increased time

spawn to strengthen the clinical application of maternal choline dietary
intake/supplementation.
Clinical Application
- Choline is generally not
part of prenatal vitamins
“bulky nutrient”

- Could take an additional supplement or

meet AI from the

diet.
Clinical Application
Choline Education Handouts
http://cholinecouncil.com/health_professional/index.php

http://vitacholine.com/healthy-ways-to-increase-choline-intake/
Questions?
References
1. Zeisel, S.H. (2012). A brief history of choline. Annals of nutrition & metabolism, 61(3), 254-8.
2. Food and Nutrition Board, Institute of Medicine. Dietary Reference Intakes: Thiamin, Riboflavin, Niacin, Vitamin B-6, Vitamin B012, Pantothenic Acid, Biotin, and Choline.
Washington, D.C.: National Academy of Sciences; 1998. pp. 390–422.
3. Cho E, Zeisel SH, Jacques P, Selhub J, Dougherty L, Colditz GA, Willett WC. Dietary choline and betaine assessed by food-frequency questionnaire in relation to plasma total
homocysteine concentration in the Framingham Offspring Study. Am J Clin Nutr 2006;83(4):905–11.
4. USDA. http://www.ars.usda.gov/SP2UserFiles/Place/12354500/Data/Choline/Choln02.pdf
5. Caudill, Marie A. Pre- and Postnatal Health: Evidence of Increased Choline Needs. J Am Diet Assoc. 2010 Aug;110(8):1198-206. doi: 10.1016/j.jada.2010.05.009.
6. Corbin, K. D., & Zeisel, S. H. (2012). Choline metabolism provides novel insights into nonalcoholic fatty liver disease and its progression. Current opinion in gastroenterology, 28(2),
159-65.
7. Shaw GM, Carmichael SL, Yang W, Selvin S, Schaffer DM. Periconceptional dietary intake of choline and betaine and neural tube defects in offspring. Am J Epidemiol 2004;160:102–9.
8. Meck WH1, Williams CL.Metabolic imprinting of choline by its availability during gestation: implications for memory and attentional processing across the lifespan. Neurosci Biobehav
Rev. 2003 Sep;27(4):385-99.
9. Yan, J. et al. Pregnancy alters choline dynamics: results of a randomized trial using stable isotope methodology in pregnant and nonpregnant women, The American Journal of Clinical
Nutrition, Volume 98, Issue 6, 1 December 2013, Pages 1459–1467
10. Caudill, M. A., Strupp, B. J., Muscalu, L., Nevins, J. E. H., Canfield, R. L. Maternal choline supplementation during the third trimester of pregnancy improves infant information
processing speed: a randomized, double-blind, controlled feeding study. FASEB J. 2018 Apr;32(4):2172-2180. doi: 10.1096/fj.201700692RR. Epub 2018 Jan 5.

11. Ross, R. G., Hunter, S. K., McCarthy, L., Beuler, J., Hutchison, A. K., Wagner, B. D., … Freedman, R. (2013). Perinatal choline effects on neonatal pathophysiology related to later
schizophrenia risk. The American Journal of Psychiatry, 170(3), 290–298. https://ajp-psychiatryonline-org.proxy.library.cornell.edu/doi/pdfplus/10.1176/appi.ajp.2012.12070940
12. Carol L Cheatham, Barbara Davis Goldman, Leslie M Fischer, Kerry-Ann da Costa, J Steven Reznick, Steven H Zeisel; Phosphatidylcholine supplementation in pregnant women
consuming moderate-choline diets does not enhance infant cognitive function: a randomized, double-blind, placebo-controlled trial, The American Journal of Clinical Nutrition, Volume
96, Issue 6, 1 December 2012, Pages 1465–1472, https://doi-org.proxy.library.cornell.edu/10.3945/ajcn.112.037184
13. Caroline E. Boeke, Matthew W. Gillman, Michael D. Hughes, Sheryl L. Rifas-Shiman, Eduardo Villamor, and Emily Oken. Choline Intake During Pregnancy and Child Cognition at
Age 7 Years. American Journal of Epidemiology. Vol. 177, No. 12. doi: 10.1093/aje/kws395