Choline: A deep delve into its role in fetal development and long-term improved cognition

The importance of ensuring for adequate choline intake during pregnancy is increasingly recognised. We now know that choline is a critical player in several physiological processes during the prenatal period and the 4th trimester.

The physiological demands for choline increase in pregnancy because it is the precursor for several biomolecules that we need considerably more of:

Acetylcholine-regulates many aspects of early brain development and supports attentional function[1].

Phosphatidylcholine- a major component of cell membranes in the brain, gut and mitochondria[2].

Sphingomyelin- the primary constituent of myelin which coats nerve cells and supports rapid cell growth.

Betaine- a methyl donor that has shown lifelong effects on gene expression and is shown to lower homocysteine levels in blood, which could reduce incidence of cardiovascular disease and other chronic diseases due to homocysteine’s damaging effect on arterial walls.[3]

As with all research it starts with the rodents! There is over 40 years of research into the effects of maternal choline for the development of their offspring’s cognitive function. Some studies naturally show no clinically significant findings but there is a larger body of evidence that supports the benefit of higher levels of choline intake in pregnancy and early life to improve attention and spatial memory in early and adolescent years and thereafter[4][5].

Moreover, high choline diets appear to be broadly neuroprotective in offspring with autism, epileptic predisposition, and down syndrome. It is shown across numerous studies to reduce the detrimental cognitive burden of these disease states[6][7][8].

Human studies on the effects of choline are still slightly limited. However, two randomized controlled studies support a positive correlation between elevated levels of placental cord plasma levels[9] or greater estimated prenatal choline consumption[10] and an increase in a child’s performance on cognitive testing. This is supported by a further two controlled studies showing an increase on an infant’s attention and orienting speed[11].

By far the most comprehensive however is a recent study out of Cornell University. It is one of the few controlled group studies conducted on humans that showed a clear correlation between the cognitive benefits for children born to mothers who received approximately double (930mg/day) the recommended daily intake of choline in their 3rd trimester compared to those mothers randomised to a dose of 480mg/day. It followed the babies through to the age of 7 where it was showed that the offspring of mothers receiving 930mg choline/day in the 3rd trimester showed a superior performance on the study’s primary endpoint (p=0.02) and a superior ability to maintain correct signal detections across the 12 minute test sessions (p=0.02) in comparison to the offspring of mothers receiving 480mg of choline/day. If you want to read more into the details of this study, I have provided a link to the paper at the bottom[12].

This study, albeit it one of few and with a smaller population size than you would ideally want, does suggest that, at present, pregnant women are advised to consume approximately 70% of the amount of choline that has shown to have an increased and positive effect on a child’s cognition and focus; begging the question, do our recommended guidelines needs to change in light of advancing evidence?

So how do we increase the amount of choline we take in?

We are human and we developed through the nutrition found in our foods first and foremost. Therefore, I have included a table of the foods that contain some of the highest values of choline below. These numbers are taken from the US database of the National Institute for Health as it was difficult to find the UK/European equivalent, therefore numbers may vary slightly but are still a great reference guide.

Food	Milligrams per serving
Beef liver, pan fried, 3 ounces	356
Egg, hard boiled, 1 large egg	147
Beef top round, seperable lean only, braised, 3 ounces	117
Soybeans, roasted, 1/2 cup	107
Chicken breast, roasted, 3 ounces	72
Beef, ground, 93% lean meat, 3 ounces	72
Fish, cod, Atlantic, cooked dry heat, 3 ounces	71
Potatoes, red, baked, flesh&skin, 1 large potato	57
Wheat germ, toasted, 1 ounce	51
Beans, Kideny, canned, 1/2 cup	45
Quinoa, cooked, 1 cup	43
Milk, 1% fat, 1 cup	43
Brussel sprouts, boiled, 1/2 cup	31
Broccoli, chopped, boiled, drained, 1/2 cup	31

Given that we have shown that values as high as 930mg of choline/day in 3rd and 4th trimester have beneficial effects in long-term cognitive health for the growing fetus it may be necessary for most to supplement with some additional choline, especially those following a vegetarian or vegan diet.

It is never too late:

• Women recruited during lactation were also split to 480mg of choline/day vs. 930mg/day. Again it was found that women allocated to the 930mg of choline/day expressed milk with higher choline quantities, beneficial to an infants rapidly developing brain. The effects may be small and there is only one study where this has been tested at present but given very limited side effects of choline supplementation, the benefits appear to outweigh any negatives. At present the recommended intake during lactation is 550mg choline/day[14].

• Further study of adults showed potential cognitive benefits and protective effects of increased choline consumption in later age, be it through food or a combination of food and supplements[15]. A positive correlation was found between elevated choline serum levels and decreased brain atrophy and white matter hypersensitivity, two hallmarks of Alzheimer’s disease and memory loss. To note, the upper range of choline found in serum of participants was below the recommended daily intake of 425mg for women and 550mg for men and yet there was still clinical significance (p=0.01).

Negative effects of choline?

Choline supplementation is well-tolerated and unlikely to cause harm. Mild adverse effects, such as hypotension, body odor and nausea are only encountered at concentrations more than a magnitude higher than recommended intake levels (>7.5g/day)[16]

Key Points:

1. Choline can be synthesized in the body, but not enough to support the needs of a growing life. At present women are advised to ensure an intake of 450mg of choline per day, increasing to 550mg per day if breastfeeding. This is best obtained through a balanced, healthy diet with oral supplementation if required.

2. Choline is shown to help reduce Neural Tube defects, and support the healthy growth of the placenta.

3. More research is required but studies in both rodent and human populations show long-term, positive effects on cognition in offspring born to mothers with higher choline in their diet.

4. Choline is also shown to be neuroprotective in conditions that can predispose a child to decreased cognition in later life, as seen in rodent models in autism, epileptics and downs syndrome. This research is yet to be extended to a human population.

5. A dosing of 930mg of choline in the 3rd and 4th trimester shows positive effects on offspring in humans and rodents, with limited negative outcomes, none of which detrimental long-term to fetus or mother.

References

[1]Abreu-Villaça Y, Filgueiras CC, Manhães AC. Developmental aspects of the cholinergic system. Behav Brain Res. 2011;221(2):367-378. doi:10.1016/J.BBR.2009.12.049

[2] Schuler MH, Di Bartolomeo F, Mårtensson CU, Daum G, Becker T. Phosphatidylcholine Affects Inner Membrane Protein Translocases of Mitochondria. J Biol Chem. 2016;291(36):18718-18729. doi:10.1074/jbc.M116.722694

[3] Margreet R Olthof, Elizabeth J Brink, Martijn B Katan, Petra Verhoef, Choline supplemented as phosphatidylcholine decreases fasting and postmethionine-loading plasma homocysteine concentrations in healthy men, The American Journal of Clinical Nutrition, Volume 82, Issue 1, July 2005, Pages 111–117, https://doi.org/10.1093/ajcn/82.1.111

[4]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;27(4):385-399. doi:10.1016/S0149-7634(03)00069-1

[5]Signore C, Ueland PM, Troendle J, Mills JL. Choline concentrations in human maternal and cord blood and intelligence at 5 y of age. Am J Clin Nutr. 2008;87:896-902. doi:10.1093/ajcn/87.4.896

[6]Langley EA, Krykbaeva M, Blusztajn JK, Mellott TJ. High maternal choline consumption during pregnancy and nursing alleviates deficits in social interaction and improves anxiety-like behaviors in the BTBR T+Itpr3tf/J mouse model of autism. Behav Brain Res. 2015;278:210-220. doi:10.1016/j.bbr.2014.09.043

[7]Powers BE, Kelley CM, Velazquez R, et al. Maternal choline supplementation in a mouse model of Down syndrome: effects on attention and nucleus basalis/substantia innominata neuron morphology in adult offspring. Neuroscience. 2017;340:501-514. doi:10.1016/J.NEUROSCIENCE.2016.11.001

[8]Yang Y, Liu Z, Cermak JM, et al. Protective effects of prenatal choline supplementation on seizure-induced memory impairment. J Neurosci. 2000;20(22):RC109. doi:10.1523/JNEUROSCI.20-22-j0006.2000

[9]Wu BTF, Dyer RA, King DJ, Richardson KJ, Innis SM. Early second trimester maternal plasma choline and betaine are related to measures of early cognitive development in term infants. PLoS One. 2012;7:e43448. doi:10.1371/journal.pone.0043448

[10]Boeke CE, Gillman MW, Hughes MD, Rifas-Shiman SL, Villamor E, Oken E. Choline intake during pregnancy and child cognition at age 7 years. Am J Epidemiol. 2013;177:1338-1347. doi:10.1093/aje/kws395

[11]Caudill MA, Strupp BJ, Muscalu L, Nevins JEH, Canfield RL. Maternal choline supplementation during the third trimester of pregnancy improves infant information processing speed: a randomized, double-blind, controlled feeding study. FASEB J. 2018;32:2172-2180. doi:10.1096/fj.201700692RR

[12]Bahnfleth, C.L., Strupp, B, J et.al. Prenatal choline supplementation improves child sustained attention: A 7-year follow-up of a randomized controlled feeding trial, The FASEB Journal, 28 December 2021, https://doi.org/10.1096/fj.202101217R

[13] U.S. Department of Agriculture, Agricultural Research Service. FoodData Central, 2019.

[14] Davenport C, Yan J, Taesuwan S, Shields K, West AA, Jiang X, Perry CA, Malysheva OV, Stabler SP, Allen RH, Caudill MA. Choline intakes exceeding recommendations during human lactation improve breast milk choline content by increasing PEMT pathway metabolites. J Nutr Biochem. 2015 Sep;26(9):903-11. doi: 10.1016/j.jnutbio.2015.03.004. Epub 2015 Apr 15. PMID: 26025328.

[15] Coreyann Poly, Joseph M Massaro, Sudha Seshadri, Philip A Wolf, Eunyoung Cho, Elizabeth Krall, Paul F Jacques, Rhoda Au, The relation of dietary choline to cognitive performance and white-matter hyperintensity in the Framingham Offspring Cohort, The American Journal of Clinical Nutrition, Volume 94, Issue 6, December 2011, Pages 1584–1591, https://doi.org/10.3945/ajcn.110.008938

[16]Institute of Medicine (US) Standing Committee on the Scientific

Evaluation of Dietary Reference Intakes and its Panel on Folate, Oth-

er B Vitamins, and Choline. Dietary Reference Intakes for Thiamin,

Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic

Acid, Biotin, and Choline. Washington (DC): National Academies

Press (US); 1998.