Metagenics
Choline
Pregnancy and Post Natal Essential
Supports healthy pregnancy and foetal development.
- Promotes healthy pregnancy and foetal development
- Reduces the risk of congenital defects
- Significantly improves foetal cognitive development and infant brain function
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BENEFITS
CLINICALLY PROVEN;
Promotes Maternal and Foetal Health
Required for the formation of new blood vessels within the placenta and uterus
Supports delivery of essential nutrients to the foetus
Participates in the regulation of embryonic development and healthy genomic expression
Lowers risk of congenital malformations
Required for rapid foetal growth
Regulates cell membrane biosynthesis and myelination of the central nervous system
Supports neurogenisis, differentiation, brain function and development
Deficiency is linked with increased risk of Autism and irreversible changes in offspring memory function.
Enhances visual memory and information processing speeds in offspring
Reduces the sensitivity of the foetus to maternal stress
Provides protective benefits to DNA that span across multiple generations
Positively influences breast milk composition
Supports healthy methylation
Supports individuals with MTFHR gene mutations
Maintains healthy liver function
CHOLINE AND CHOLINE DEFICIENCY
Choline is an essential nutrient required for the synthesis of several important compounds, including acetylcholine, choline phospholipids and betaine.[1]
Through these compounds, choline supports the production of neurotransmitters, cellular membranes, and neuronal networks, cell division and enhances DNA methylation.
As such, choline facilitates many vital functions in the body. Australian research published in 2019 indicates that less than 10% of the national population consumes the adequate choline intake (AI),[2]consistent with nutritional data indicating insufficient dietary intake of choline in Western countries.[3]
Choline is associated with enhanced pregnancy outcomes in mothers and infants,[4],[5]in addition to promoting cognitive function[6]and reducing the risk of hepatic disease.[7]As such, choline is an important nutrient required to support essential functions across the lifespan of an individual.
Individuals who avoid the consumption of meat and animal products are at greater risk of choline inadequacy.[16] Further to this, researchers have found that many women do not meet the AI levels of choline during pregnancy,[17]resulting in reduced choline availability during foetal development.
Choline insufficiency is also prevalent in children, as studies indicate that only 22.5% of European kindergarteners recruited from a local province consumed adequate choline.[18]Moreover, data in children with autism spectrum disorder (ASD) indicates that 60% to 93% of participants consumed less than the recommended intake.[19]
Furthermore, inadequate choline levels are associated with insulin resistance,[23]lower bone mineral density,[24]and liver cancer risk.[25]
PROMOTES MATERNAL AND FOETAL HEALTH
The importance of choline in early life is highlighted by:
Large amounts of choline being distributed to the foetus during gestation[48];
Pregnancy causing depletion of maternal choline[49]
The placenta contains approximately 50 times more choline that maternal blood[50].
Neonates being born with levels six to seven times higher than maternal blood concentrations[51]; and
Large amounts of choline being present in human milk.[52]
These factors indicate an increased requirement for choline in pregnant women and neonates. In early pregnancy, choline is required for the growth of maternal organs, specifically, for angiogenesis within the placenta and uterus,[53]by limiting antiangiogenic marker, soluble fms-like tyrosine kinase-1 (sFLT1).[54]
Further, choline supports maternal kidney growth[55]in response to increased blood volume from first trimester until birth.[56]
Essential for DNA methylation, choline participates in the regulation of embryonic development and healthy genomic expression[57] by providing methyl groups (via betaine) for use in modulating genetic expression. Specifically, the addition of methyl groups can silence gene expression, whilst the removal of methyl groups can activate gene activity.
Betaine-derived methyl groups can enter the placenta via SAMe, supporting DNA methylation in the foetus. Moreover, placental synthesis of ACh also helps to methylate the placental genome, supporting placental maturation and parturition at birth (Figure 4).[58]
Additionally, choline supports delivery of essential nutrients to the foetus, in particular, increasing delivery of omega-3 fatty acid, docosahexaenoic acid (DHA), via lipoproteins. Increased lipid transport is mediated by choline availability, which supports increased hepatic lipoprotein synthesis during pregnancy.
During gestation, low-density lipoprotein (LDL) increases by 46%, high-density lipoprotein (HDL) by 23% and very low-density lipoprotein (VLDL) by 36%.[60]By facilitating lipoprotein production, choline enhances the delivery of DHA to the foetus.[61],[62]
Choline is also required for rapid foetal growth and cell membrane biosynthesis,[63],[64] in addition to supporting neurogenesis, neuronal cell division and differentiation, and healthy genetic expression.[65]
Due to its importance for hippocampal development involved in memory function,[66] insufficient maternal choline intake has been associated with irreversible changes in offspring memory function.
[67]
Conversely, greater intakes have been shown to enhance visuospatial and auditory memory in an animal model.[68] Choline status during the first trimester is associated with enhanced cognitive development in human infants,[69] whilst inadequate intakes during pregnancy have been linked to reduced cognitive function seven years post-birth.[70]
As well as contributing to structural development of the brain and nervous system, maternal choline intake has been demonstrated to alter nervous system function by protecting the developing foetal neuroendocrine system.
In the third trimester, adequate choline intake favorably alters the epigenetic programming within the placental and foetal hypothalamic pituitary adrenal (HPA) axis, reducing the sensitivity of the foetus to maternal stress.[71]As such, maternal choline intake may counter some of the adverse effects of prenatal stress in the offspring.
Furthermore, research indicates that choline status provides protective benefits to DNA that span across multiple generations.[72]
To measure the transgenerational effects of choline supplementation, pregnant mice were given choline throughout gestation up to the 21 days after birth. Analysis of the brain tissue of the offspring of these choline-supplemented mice showed reduced brain atrophy and microglial inflammation; demonstrating protective transgenerational effects in mammalian offspring.[73]
SUPPORTS BRAIN FUNCTION AND NEURAL GROWTH
Beyond foetal needs, choline is an important nutrient across the lifespan. In both children and adults, it regulates cell membrane biosynthesis, myelination of the central nervous system (via the production of sphingomyelin),[74] as well as neuronal proliferation, differentiation, migration, maturation, plasticity and synapse formation (by supporting ACh production).[75]
Reduced levels of choline and its metabolites have been observed in the cerebral cortex and plasma of individuals with brain atrophy and neuronal damage.[76],[77]Further to this, reduced PC levels in red blood cells are associated with reduced brain levels of omega-3 fatty acid, DHA, correlated with smaller brain volume and vascular patterns of cognitive decline.[78]Thus, the availability of choline is important for maintaining healthy neurocognitive function.
Further, choline availability influences neural progenitor cells (NPCs), which stimulate neural growth in animal models.[79] NPC development is dependent on methylation, therefore choline insufficiency can hinder NPC function.
For example, low choline status was shown to upregulate microRNA (miR-129-5p) expression in the brain, causing the downregulation of epidermal growth factor receptor (EGFR), disrupting NPC self-renewal and cortical neurogenesis. Researchers found that restoring methylation potential in NPCs reversed low choline-induced defects,[80] indicating that neural growth is choline-dependent.
ENHANCED INFANT COGNITIVE FUNCTION
Research indicates that greater maternal dietary choline intake enhances visual memory and information processing speeds in offspring.
In a study designed to assess this, 895 pregnant women recorded their food intake over the first and second trimesters, and seven years later their children’s cognitive function was assessed. Despite average intakes being below the recommended RDI for pregnancy (328 mg/d choline), offspring of mothers in the top quartile of choline intake in the second trimester scored 1.4 points higher in cognitive assessment compared to the bottom quartile (p=0.03).[90]
Similarly, in 154 mother-child pairs, researchers investigated associations between plasma choline levels at 16 and 36 weeks gestation in relation to infant neurodevelopment at 18 months. Outcomes of the study revealed that even when mothers consumed less than the choline RDI (participants consumed 383 mg ± 98.6), maternal choline status at 16 weeks gestation shared a statistically significant relationship with infant neurodevelopment (p=0.009).[91]
Further to this, research examining the effects of choline supplementation in the third trimester of pregnancy reveals that a total intake of either 480 mg/d or 930 mg/d enhances infant information processing speed and visuospatial memory.[92]
Twenty-four women were divided into two groups, consuming 380 mg/d of dietary choline in addition to either 100 or 550 mg/d (a total intake of either 480 mg/d or 930 mg/d), between 27 weeks gestation and delivery. After birth, infants performed cognitive tests measuring eye movement as a proxy for mental processing speed. At four, seven, 10 and 13 months of age, the mean reaction time to stimulus was significantly faster for infants whose mothers consumed 930 mg/d of total choline (p=0.03). This indicates that maternal choline supplementation during the third trimester of pregnancy supports offspring cognitive development.
This intervention also resulted in enhanced offspring cognition at seven years of age.[94]Children participated in neurocognitive assessment, involving a sustained attention task (SAT), which required focus to determine the presence or absence of visual signals at 17, 29 and 50 minutes. Mean SAT scores and mean percentage of correct responses were significantly greater for the 930 mg/d group compared to 480 mg/d group, supporting the benefits of choline intake during pregnancy.
Research indicates that choline supports cognitive performance in healthy populations. For example, in 28 adults supplemented with 800 mg/d of choline (equivalent to 2 g/d choline bitartrate), treatment was shown to enhance mental performance 70 minutes after ingestion.[111]Participants were randomised to receive either choline or placebo, and then performed computational tasks designed to assess spatial working memory and visuomotor skill. Participants supplemented with choline performed with greater visual accuracy compared to the placebo group (p=0.03). In addition, choline intake was shown to significantly decrease pupil size, a cognition-sensitive biomarker correlated with reaction time and task execution, after 20 and 40 minutes post choline ingestion (p<0.05). As ACh production peaks 20 to 40 minutes after choline ingestion,[112]this suggests choline supplementation enhances cognitive function by supporting ACh synthesis.
A Study of healthy women in the third trimester of pregnancy (n=26).[113] took 100 mg choline chloride vs. 550 mg choline chloride + 380 mg /d dietary intake (total of 480 mg/d or 930 mg/d) for 12 weeks
At 4, 7, 10 and 13 months of age, mean reaction time during neurocognitive tasks was significantly faster for infants born to mothers consuming 930 mg/d of total choline (p=0.03)
Results indicated that 550 mg/d of choline in addition to dietary intake enhances childhood neurocognitive function in a safe and effective manner.
From this study, the children at the age of 7 years with the higher choline intake group (930 mg/d) were more likely to correctly solve problem solving tasks in a single attempt (p=0.03), indicating enhanced executive function[114,115]. They also demonstrated better performance within sustained attention tasks, and percentage of correct responses (p=0.02)[116]
Blood samples from placenta and umbilical cord tissue indicated that higher maternal intake (930 mg/d) yielded greater methylation of cortisol regulating genes, corticotrophin release hormone (CRH) and lower placental CRH transcription[117].
Pregnant women who supplemented with 550 mg/d exhibit favourable epigenetic outcomes of reduced foetal HPA axis reactivity and protection from elevated stress hormone exposure[117].
REDUCED RISK OF ADVERSE OUTCOMES
NTD are congenital malformations of the central nervous system (CNS) due to failed neural tube closure during embryogenesis.[95]As a result, anencephaly and spina bifida can develop in neonates.[96]Folic acid supplementation reduces the incidence of NTD by 50% to 75%.[97]However, multiple studies also indicate that choline is protective against NTD-affected pregnancy.[98]
For example, in a study examining the nutritional data from 424 NTD cases matched with controls, NTD risk estimates were lower for women whose diets were rich in sources of choline.[99]These findings have been supported by a later study in 180,000 pregnant women, which measured serum levels of various nutrients (including folate, vitamin B12, methionine and choline) between the 15th and 18th week of gestation.
Results indicated that women with relatively high levels of choline had a lower risk of NTD-affected pregnancy (congenital malformations).[100]
Both studies controlled for the preventative effects of folate intake, suggesting that both nutrients independently reduce NTD risk.
Another potential adverse outcome in pregnancy is foetal alcohol spectrum disorder (FASD), caused by alcohol intake during pregnancy.
FASD is associated with permanent brain damage, congenital anomalies and growth restriction, along with other functional deficits.[101]Several studies indicate the protective effects of choline in FASD.[102]
A systematic review and meta-analysis of preclinical studies indicate choline supplementation ameliorates epigenetic and molecular changes that contribute to the abnormalities seen in FASD, as well as improving gross motor skills, and impairments in memory and executive function.[103]
In a study of 372 pregnant women classified as moderate to heavy alcohol consumers, patients were divided into two groups receiving either 750 mg/d of choline alongside a multivitamin and mineral (MVM) supplement, or the MVM supplement alone.[104]Choline supplementation in combination with MVM was found to improve basic learning mechanisms in offspring compared to MVM alone. As such, choline supplementation can help to reduce the effects of FASD in pregnancy.
When given directly to children, choline can also reduce cognitive deficits of FASD. In a study conducted in 60 FASD-affected children, participants were administered 500 mg/d of choline for nine months to determine the effects of choline on memory function.[105]
Children aged two and a half to four years old showed a 12 to 14% increase in pre-verbal memory assessment outcomes, consistent with the timing of hippocampal development in early childhood; suggesting that enhancement of post-natal hippocampal function in children with cognitive deficits.
ENHANCED DHA DELIVERY TO INFANT
Evidence suggests that the combination of choline and DHA during pregnancy enhances hippocampal development compared to choline or DHA alone.[106]
Research in 24 preterm infants between 24 and 31 weeks (gestational age) found concurrent choline and DHA supplementation for 10 days significantly increased DHA bound to PC (the form present in all tissue and brain grey matter) compared to DHA alone (63% vs 35%, p<0.001).[107]
Patients were randomised into four groups, receiving either normal enteral nutrition (control group), 30 mg/kg/d of choline, 60 mg/kg/d of enteral DHA, or 30 mg/d of choline plus 60 mg/kg/d of DHA. Plasma choline and choline metabolites assessed after the study indicated that concurrent choline and DHA supplementation enhanced the uptake of DHA in preterm infants,[108]providing the DHA required for healthy brain development.
LACTATION SUPPORT
Demand for choline is also high during lactation.[109] Research in 28 lactating mothers consuming either 480 mg/d or 930 mg/d of choline for 10 to 12 weeks demonstrated enriched choline levels in breast milk.[110]
Patients were randomised into active and control groups, with the treatment group further divided into mothers supplementing 100 mg/d of choline alongside 380 mg/d of controlled dietary intake (total of 480 mg/d), or a 550 mg supplement in addition to dietary intake (total 930 mg/d).
Greater choline intake positively influenced breast milk composition, with significantly higher concentrations found in the 930 mg/d group compared to the 480 mg/d group. As such, choline supplementation in breastfeeding enhances infant choline intake, supporting growth and development.
SUPPORTS HEALTHY METHYLATION
Methylation is the chemical process whereby a methyl group (CH3) is added to a substrate to catalyse biochemical reactions essential for healthy cell function.
These include creatine synthesis (essential for ATP mobilisation),[36]phospholipid production, cellular communication, epigenetic regulation and DNA repair.[37]
Due to these important roles, poor methylation is associated with a number of disease states; however, specific nutrients that act as methyl donors can help promote healthy methylation.[38]
An important precursor for betaine production, choline provides 60% of the body’s methyl groups.[39]Betaine donates three methyl groups, and, combined with folate in the form of 5-methyltetrahydrofolate (5-MTHF), facilitates the production of S-adenosylmethionine (SAMe),[40]a major methyl donor.
After donating its methyl groups, SAMe is then oxidised into S-adenosyl-homocysteine (SAH), forming homocysteine (Hcy), which then converts back to methionine in in the presence of adequate methyl donors.[41],[42]When the nutritional status of either choline or 5-MTHF is insufficient, Hcy can accumulate,[43]which is a marker of cardiovascular and neurologic disease risk.
However, research indicates that choline supplemented at 1.0 g/d and 2.6 g/dlowers elevated Hcy levels, highlighting the role of choline in healthy methylation.[45]
Further to this, choline supplementation has been shown to support individuals with various genetic single-nucleotide polymorphisms (SNPs) associated with impaired methylation, including methyltetrahydrofolate reductase (MTHFR) mutations.[46]
Impaired methylation lowers methyl group availability required for PEMT activity, resulting in reduced endogenous biosynthesis of PC. This leads to greater utilisation of dietary choline to compensate for limited PEMT function.
Consequently, this limits the amount of choline available for betaine synthesis, which would normally compensate for the impaired methylation related to these SNPs. Interestingly, studies have confirmed that a total intake of 930 mg/d of choline compensates for several methylation-limiting SNPs, restoring adequate PC biosynthesis, supporting betaine availability for methylation.[47]
930 mg/d of choline compensates for several methylation-limiting SNPs, restoring adequate PC biosynthesis, supporting betaine availability for methylation
SUPPORTS LIVER FUNCTION
The consumption of choline is vital for the maintenance of healthy liver function.[81]Choline protects the liver by:
Facilitating lipoprotein synthesis for fat transportation[82];
Promoting healthy membrane composition[83]; and supporting methylation reactions (alongside folate and vitamin B12).[84]
Inadequate choline availability compromises several mechanisms that protect the liver from tissue damage. When deprived of choline, the body fails to synthesise lipoproteins, leading to the accumulation of triglycerides within the liver.[85]
Further, insufficient choline impairs mitochondrial membrane integrity within hepatocytes, and limits mitochondrial energy output required to sustain cellular functions.
Without adequate choline, cellular membranes are more susceptible to oxidative compounds and their damaging effects.[86]This, in turn, leads to the death of hepatocytes, triggering an inflammatory response and generating further damage within tissues.[87]As a result, accumulated hepatic fat (trapped by insufficient lipoprotein synthesis), compounded by chronic inflammation, leads to pathophysiological changes in liver tissue.
Such changes can range from mild hepatic fibrosis to irreversible liver damage with cancerous lesions.[88]
In fact, data indicates that decreased choline intake is significantly associated with increased liver fibrosis in post-menopausal women diagnosed with non-alcoholic fatty liver disease (p=0.02).[89] This is consistent with physiological decreases in choline synthesis after menopause, in addition to the prevalence of low intakes in women, demonstrating the critical importance of choline intake in hepatic health.
INGREDIENTS
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DIRECTIONS
Each capsule contains 225mg of Choline
Adequate intake levels of choline, per day:
Infants 0 - 6 months: 125mg
Babies 7 - 12 months: 150mg
Children, 1 -3 years: 200mg
Children, 4 - 8 years: 250mg
Children 9 - 13 years: 375mg
Adolescent Females aged 14-18: 400mg
Adolescent Males aged 14-18: 550mg
Women, aged 19 - >70: 425mg
Men: 19 - >70: 550mg
Pregnancy: 450mg.
Note: Positive test outcomes associated 930mg per day
Lactation: 550mg
EVIDENCE
References
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[2] Probst Y, Guan V, Neale E. Development of a choline database to estimate Australian population intakes. Nutrients. 2019 Apr 23;11(4). pii: E913. doi: 10.3390/nu11040913.
[3] Wallace TC, Fulgoni III VL. Assessment of total choline intakes in the United States. J Am Coll Nutr. 2016;35(2):108-12. doi: 10.1080/07315724.2015.1080127.
[4] Jiang X, Bar HY, Yan J, Jones S, Brannon PM, West AA, et al. A higher maternal choline intake among third-trimester pregnant women lowers placental and circulating concentrations of the antiangiogenic factor fms-like tyrosine kinase-1 (sFLT1). FASEB J. 2013 Mar;27(3):1245-53. doi: 10.1096/fj.12-221648. Epub 2012 Nov 29.
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[10] Lewis ED, Zhao YY, Richard C, Bruce HL, Jacobs RL, Field CJ, et al. Measurement of the abundance of choline and the distribution of choline-containing moieties in meat. Int J Food Sci Nutr. 2015;66(7):743-8. doi:10.3109/09637486.2015.1088942.
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[14] Oregon State University - Linus Pauling Institute [Internet]. Corvallis (OR): Linus Puling Institute; c2002-2018. Choline; 2003 [updated 2015 Feb; cited 2019 Mar 21]. Available from: https://lpi.oregonstate.edu/mic/other-nutrients/choline.
[15] National Health and Medical Research Council. Nutrient Reference Values for Australia and New Zealand. Choline [Internet]. Canberra (ACT): Australian Government. 2014. [Cited 2019 Mar 21]. Available from: https://www.nrv.gov.au/nutrients/choline.
[16] Wallace TC, Blusztajn JK, Caudill MA, Klatt KC, Natker E, Zeisel SH, et al. Choline: The underconsumed and underappreciated essential nutrient. Nutr Today. 2018 Nov-Dec;53(6):240-253. doi: 10.1097/NT.0000000000000302.
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[18] Reinhard Prelicz C, Lotrean LM. Choline intake and its food sources in the diet of Romanian kindergarten children. Nutrients. 2017 Aug 18;9(8). pii: E896. doi: 10.3390/nu9080896.
[19] Hamlin JC, Pauly M, Melnyk S, Pavliv O, Starrett W, Crook TA, et al. Dietary intake and plasma levels of choline and betaine in children with autism spectrum disorders. Autism Res Treat. 2013;2013:578429. doi: 10.1155/2013/578429.
[20] Fischer LM, daCosta KA, Kwock L, Stewart PW, Lu TS, Stabler SP, et al. Sex and menopausal status influence human dietary requirements for the nutrient choline. Am J Clin Nutr. 2007 May;85(5):1275-85.
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[22] Ganz AB, Shields K, Fomin VG, Lopez YS, Mohan S, Lovesky J, et al. Genetic impairments in folate enzymes increase dependence on dietary choline for phosphatidylcholine production at the expense of betaine synthesis. FASEB J. 2016 Jun 24;30(10):3321-33.
[23] Gao X, Wang Y, Sun G. High dietary choline and betaine intake is associated with low insulin resistance in the Newfoundland population. Nutrition. 2017 Jan;33:28-34. doi: 10.1016/j.nut.2016.08.005.
[24] Øyen J, Gjesdal CG, Karlsson T, Svingen GF, Tell GS, Strand E, et al . Dietary choline intake is directly associated with bone mineral density in the Hordaland health study. j nutr. 2017 apr;147(4):572-578. doi: 10.3945/jn.116.243006.
[25] Zhou RF, Chen XL, Zhou ZG, Zhang YJ, Lan QY, Liao GC, et al. Higher dietary intakes of choline and betaine are associated with a lower risk of primary liver cancer: a case-control study. Sci Rep. 2017 Apr 6;7(1):679. doi: 10.1038/s41598-017-00773-w.
[26] Caudill MA. 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. Review. PubMed PMID: 20656095.
[27] Blusztajn JK, Slack BE, Mellott TJ. Neuroprotective actions of dietary choline. Nutrients. 2017 Jul 28;9(8). pii: E815. doi: 10.3390/nu9080815.
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[29] Caudill MA. 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. Review. PubMed PMID: 20656095.
[30] Caudill MA. 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. Review. PubMed PMID: 20656095.
[31] Caudill MA. 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. Review. PubMed PMID: 20656095.
[32] Caudill MA. 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. Review. PubMed PMID: 20656095.
[33] Caudill MA. 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. Review. PubMed PMID: 20656095.
[34] Caudill MA. 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. Review. PubMed PMID: 20656095.
[35] Ganz AB, Shields K, Fomin VG, Lopez YS, Mohan S, Lovesky J, et al. Genetic impairments in folate enzymes increase dependence on dietary choline for phosphatidylcholine production at the expense of betaine synthesis. FASEB J. 2016 Jun 24;30(10):3321-33.
[36] Joncquel-Chevalier Curt M, Voicu PM, Fontaine M, Dessein AF, Porchet N, Mention-Mulliez K et al. Creatine biosynthesis and transport in health and disease. Biochimie. 2015 Dec;119:146-65. doi: 10.1016/j.biochi.2015.10.022.
[37] Williams KT, Schalinske KL. New insights into the regulation of methyl group and homocysteine metabolism. J Nutr. 2007 Feb;137(2):311-4. doi: 10.1093/jn/137.2.311.
[38] Mahmoud AM, Ali MM. Methyl donor micronutrients that modify DNA methylation and cancer outcome. Nutrients. 2019 Mar 13;11(3). pii: E608. doi:
10.3390/nu11030608.[39] Niculescu MD, Zeisel SH. Diet, methyl donors and DNA methylation: interactions between dietary folate, methionine and choline. J Nutr. 2002 Aug 1;132(8):2333S-5S.
[40] Niculescu MD, Zeisel SH. Diet, methyl donors and DNA methylation: interactions between dietary folate, methionine and choline. J Nutr. 2002 Aug 1;132(8):2333S-5S.
[41] Mehedint MG, Zeisel SH. Choline's role in maintaining liver function: new evidence for epigenetic mechanisms. Curr Opin Clin Nutr Metab Care. 2013;16(3):339-45.
[42] Obeid R. The metabolic burden of methyl donor deficiency with focus on the betaine homocysteine methyltransferase pathway. Nutrients. 2013;5(9):3481-3495.
[43] Zeisel SH, Niculescu MD. Perinatal choline influences brain structure and function. Nutr Rev. 2006; 64(4):197-203.
[44] Zeisel SH. Choline: critical role during fetal development and dietary requirements in adults. Annu Rev Nutr. 2006;26:229-50.
[45] Olthof MR, Brink EJ, Katan MB, Verhoef P. Choline supplemented as phosphatidylcholine decreases fasting and postmethionine-loading plasma homocysteine concentrations in healthy men. Am J Clin Nutr. 2005 Jul;82(1):111-7. PubMed PMID: 16002808.
[46] 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). pii: E252. doi: 10.3390/ijms18020252.
[47] Ganz AB, Shields K, Fomin VG, Lopez YS, Mohan S, Lovesky J, et al. Genetic impairments in folate enzymes increase dependence on dietary choline for phosphatidylcholine production at the expense of betaine synthesis. FASEB J. 2016 Jun 24;30(10):3321-33.
[48] Caudill MA. 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. Review. PubMed PMID: 20656095.
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WARNINGS
Pregnancy and Breastfeeding
Pregnancy
There is evidence to support the use of these ingredients during pregnancy and a review did not identify concerns for use. Doses up to 3 grams daily for pregnant women up to 18 years of age, and 3.5 grams daily for women 19 years and older are not likely to cause adverse effects.[118],[119]
Breastfeeding
Appropriate for use.
Likely safe when used orally and appropriately. Doses up to 3 grams daily for lactating women up to 18 years of age, and 3.5 grams daily for women 19 years and older are not likely to cause adverse effects.[120],[121]
MGXMETC
