December 2020

Based on the Australian Food Nutrient Database, less than 10% of the population consume the recommended Adequate Intake (AI) of choline, with estimated intakes in pregnant women aged 14 to 50 years at only 150-250 mg per day,[i] compared to the established AI of 415-440 mg.[ii] More importantly though, evidence suggests that pregnant women require substantially more choline than is currently recommended, especially during the third trimester.[iii] In addition, dietary choline usually exists in various water-soluble and lipid-soluble forms that are differently metabolised and therefore differently impact foetal growth and development.[iv],[v] Hence, consistent and adequate choline supplementation offers a practical way to ensure that mum and baby receive the right amounts and the full benefits that choline can provide.

Physiological Importance of Choline during Pregnancy

Choline is an essential nutrient for humans that is closely associated with the B-vitamin family. It is found in small amounts in animal foods and those containing lecithin (i.e. egg yolks, liver, organ and muscle meats, shrimp, salmon, soybeans, wheat germ, etc.).[vi],5 It can also be synthesised in the body, however, endogenous production depends on the methyl exchange relationship between choline, folate, vitamin B12 and methionine.2

Choline is required for the synthesis of the neurotransmitter acetylcholine, the methyl donor betaine, various cell membrane constituents (phospholipids and sphingomyelin), as well as to regenerate methionine from homocysteine.2,4,6,[vii] Ensuring an adequate intake of choline during pregnancy is particularly important as choline is critical for numerous metabolic and physiologic processes involved in placental function, neurodevelopment and epigenetic programming (see figure 1 below).1,[viii],[ix],[x]

Figure 1 | An overview of the effects of maternal choline intake during pregnancy.8

A recent systematic review on the importance of choline for neurological development and brain function in the offspring suggests that supplementing the maternal or child's diet with choline over the first 1000 days of life (from conception to a child’s second birthday) could:5

support normal brain development
protect against neural and metabolic insults (including alcohol)
improve neural and cognitive functioning and dampen intellectual disability

Endogenous Production and Supplementation with Choline During Pregnancy

In the liver, choline can be utilised in two different ways: it is either converted to phosphatidylcholine (PC, the major phosphatide in neuronal membranes) through the cytidine diphosphate (CDP)-choline pathway (CDP-CP) or it can be oxidized to produce betaine, a methyl group used to produce PC via the de novo phosphatidylethanolamine N-methyltransferase (PEMT) pathway (PEMT-PC). Both pathways are upregulated during the third trimester of pregnancy, however, PEMT-derived PC is preferentially partitioned to the developing foetus. Choline itself is used to support the PEMT pathway because endogenous production is not sufficient to support the body’s biological processes.8,[xi],[xii]

However, even women who consume 480 mg choline per day during pregnancy have been shown to have 40–60% lower circulating concentrations of choline-derived methyl metabolites, as well as diminished partitioning of choline towards betaine.12 In contrast, a higher dose of 930 mg choline per day restores the partitioning of choline between the oxidative and CDP-choline pathways and increases circulating concentrations of choline-derived methyl metabolites. Moreover, the higher intake beneficially influenced a number of pregnancy outcomes, including neonatal stress reactivity, faster information processing speed among infants, and better memory in children at 7 years of age.3

Another important factor that influences choline requirements is that women of reproductive age commonly exhibit genetic polymorphisms, such as those involving the oestrogen-induced enzyme PEMT.[xiii]

Effects of Maternal Choline Supplementation on Infant Information Processing

A recent single-centre feeding intervention study with a randomized, double-blind, parallel-group controlled design examined the effects of maternal choline supplementation during the third trimester of pregnancy on infant cognition. Women either received 480 mg (n=13) or 930mg choline per day (n=13) until delivery. Infant information processing speed and isuospatial memory were tested at 4, 7, 10, and 13 months of age (n = 24), with mean reaction time averaged across the four ages found to be significantly faster in infants of mothers who received the higher dosage of choline (22.6 ms faster, p = 0.03) than that observed in the comparative group. Furthermore, infants of mothers who received 480 mg choline per day had a significant linear dose–response showing that faster infant processing speed was associated with a greater number of days of foetal exposure to this maternal choline dose. The study hence demonstrated that maternal consumption of approximately twice the recommended dose of choline (930 mg per day) during the last trimester improves infant information processing speed, but also that even modest increases in maternal choline intake during pregnancy (480 mg per day) are able to produce cognitive benefits in the offspring.[xiv]

Common Genetic Risk Factors that alter Choline Dynamics in Pregnant, Lactating, and Non-Pregnant Women Consuming Choline

Another controlled feeding study investigated how common genetic risk factors alter choline dynamics in pregnant, lactating, and non-pregnant women (n=75) who consumed 480 or 930 mg choline per day for 10–12 weeks. The study demonstrated that common genetic variants in choline metabolizing genes alter the metabolic signature of dietary choline in three ways:

Its use as a methyl donor
Its partitioning between betaine and CDP-PC synthesis
Its distribution between PEMT-PC and CDP-PC

These results provide compelling evidence that common single nucleotide polymorphisms (SNPs) modulate choline partitioning in women of reproductive age who consume recommended choline intakes and that these metabolic differences potentially contribute to disease pathogenesis and prognosis over the long-term.11

Clinical Application

These findings highlight the need for practitioners to prescribe higher doses of choline than those currently recommended, especially in the third trimester to ensure optimal health benefits for mum and baby.

To further capitalise on these health benefits, choline is best taken along with other nutrients, such as

Activated forms of vitamin B2, B6, B12 and folate to support methylation and expression of genetic material (DNA)[xv],[xvi]
Copper, iodine, iron, selenium, zinc, vitamin B6 and B12, folate, and vitamin K to support early brain development10,[xvii]
Docosahexaenoic acid (DHA) to further support neurodevelopment[xviii],[xix]

References

[i] Probst Y, Guan V, Neale E. Development of a Choline Database to Estimate Australian Population Intakes. Nutrients. 2019 Apr 23;11(4):913.

[ii] National Health and Medical Research Council (NHMRC) Nutrient Reference Values for Australia and New Zealand 2006.

[iii] Yan J, Jiang X, West AA, Perry CA, Malysheva OV, Brenna JT et al. Pregnancy alters choline dynamics: results of a randomized trial using stable isotope methodology in pregnant and nonpregnant women. Am J Clin Nutr. 2013 Dec;98(6):1459-67.

[iv] Wiedeman AM, Barr SI, Green TJ, Xu Z, Innis SM, Kitts DD. Dietary Choline Intake: Current State of Knowledge Across the Life Cycle. Nutrients. 2018 Oct 16;10(10):1513.

[v] Derbyshire E, Obeid R. Choline, Neurological Development and Brain Function: A Systematic Review Focusing on the First 1000 Days. Nutrients. 2020 Jun 10;12(6):1731.

[vi] Gropper SS & Smith JL. Advanced Nutrition and Human Metabolism. 6th ed. Australia: Wadsworth CENGAGE Learning; 2013.

[vii] Kohlmeier. Nutrient Metabolism. London: Academic Press; 2003.

[viii] Korsmo HW, Jiang X, Caudill MA. Choline: Exploring the Growing Science on Its Benefits for Moms and Babies. Nutrients. 2019 Aug 7;11(8):1823.

[ix] Zeisel SH. Nutrition in pregnancy: the argument for including a source of choline. Int J Womens Health. 2013 Apr 22;5:193-9.

[x] Schwarzenberg SJ, Georgieff MK. Advocacy for Improving Nutrition in the First 1000 Days to Support Childhood Development and Adult Health. Pediatrics. 2018 Feb;141(2). pii: e20173716.

[xi] Ganz AB, Cohen VV, Swersky CC, Stover J, Vitiello GA, Lovesky J et al. Genetic Variation in Choline-Metabolizing Enzymes Alters Choline Metabolism in Young Women Consuming Choline Intakes Meeting Current Recommendations. Int J Mol Sci. 2017 Jan 26;18(2):252.

[xii] Yan J, Jiang X, West AA, Perry CA, Malysheva OV, Devapatla S et al. Maternal choline intake modulates maternal and fetal biomarkers of choline metabolism in humans. Am. J. Clin. Nutr. 2012, 95, 1060–1071.

[xiii] da Costa KA et al. Identification of new genetic polymorphisms that alter the dietary requirement for choline and vary in their distribution across ethnic and racial groups. FASEB J. 2014 Jul;28(7):2970-8.

[xiv] 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 Apr;32(4):2172-2180.

[xv] Anderson OS, Sant KE, Dolinoy DC. Nutrition and epigenetics: an interplay of dietary methyl donors, one-carbon metabolism and DNA methylation. J Nutr Biochem. 2012 Aug;23(8):853-9.

[xvi] Niculescu MD, Zeisel SH. Diet, methyl donors and DNA methylation: interactions between dietary folate, methionine and choline.J Nutr. 2002 Aug; 132(8 Suppl):2333S-2335S.

[xvii] Ramakrishnan U et al. Effect of women’s nutrition before and during early pregnancy on maternal and infant outcomes: a systematic review. Paediatr Perinat Epidemiol. 2012;Suppl 1:285-301.

[xviii] Morse NL. Benefits of docosahexaenoic acid, folic acid, vitamin D and iodine on foetal and infant brain development and function following maternal supplementation during pregnancy and lactation. Nutrients. 2012 Jul;4(7):799-840.

[xix] Karr JE, Alexander JE, Winningham RG. Omega-3 polyunsaturated fatty acids and cognition throughout the lifespan: a review. Nutr Neurosci. 2011;14(5):216-25.

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