students who completed three-day food diaries, from which .... tendency to choose low-fat food options.4. Hot Topic .... vegetarians), planning meals and eating a.
Choline Emerging interest and potential roles in pregnancy H. Chadwick, BSc Human Nutrition, and Dr E Derbyshire, PhD, RNutr, Senior Lecturer in Nutritional Physiology, Manchester Metropolitan University.
It is well known that folic acid is needed for maternal and infant health during the reproductive years but now scientists have discovered that another nutrient that may also be beneficial. Choline appears to play a key role in supporting fetal brain development and neurotransmitter synthesis. This B-vitamin is found in a variety of foods, although eggs, meat and dairy products are some of the richest sources. Unfortunately, trends toward low-fat diets mean that this nutrient has a tendency to be under-consumed and is presently not included in all pregnancy supplements. This article sets out to review latest evidence within this field, providing information on how women of childbearing age may adapt their diets to include suitable levels of choline-rich foods.
Introduction Choline was initially discovered in 1862 by a scientist named Adolf Strecker when it was first extracted from ox bile (bile in Greek can be translated to chole).1 Choline has wide-ranging roles in the human body, from cell structure to neurotransmitter synthesis which are especially important during pregnancy when these processes are more pronounced.2 For example, in terms of cell structure choline is needed for cell membrane synthesis (which contains phosphatidylcholine). In the case of neurotransmitter synthesis, choline is acetylated (a reaction that joins acetyl onto choline), to form the brain neurotransmitter acetylcholine.3 With the rise of genetic testing it has come to light that some women may have underlying genetic defects, also known as single nucleotide polymorphisms (SNPs; where some of the DNA bases are incorrect) which could affect their ability to produce choline themselves efficiently, placing a greater need on eating enough choline-rich foods.4 For women without SNPs, the hormone estrogen normally plays a key role in stimulating the phosphatidylethanolamine-N-methyltransferase (PEMT) gene, which leads to the synthesis of phosphatidylcholine and then choline (see Figure 1). However, for some women (around as many as 50%) presence of a SNP in the PEMT gene may mean they are unresponsive to estrogen and subsequently lead to lower levels of endogenous choline production.2, 4
Choline intakes
Figure 1: The Metabolism of Choline Phosphatidylcholine Estrogen PEMT (Phosphatidylethanolamine-N-methyltransferase) Phosphatidylethanolamine
There is also growing evidence that choline may be able to alter fetal gene expression; a factor that could affect the long-term health of the infant.5 In brief, gene expression, is whether a gene expresses its trait weakly or prominently and the degree of methylation (number of methyl CH3 groups joined to certain DNA region) plays a key role in regulating this.6 Choline acts as a methyl donor, which can play a role in gene silencing i.e. of genes that may potentially be unfavourable to infant health. Although further research is needed these mechanisms may directly affect elements of infant brain development which could have lasting effects.7 While there has been an emergence of new evidence in this area, awareness and knowledge of choline amongst health professionals appears to be rather limited. One survey sponsored by the American Egg Board, using responses obtained from 252 health professionals (dietitians and physicians) found that 10 per cent were ‘moderately familiar’ with the nutrient choline and likely to recommend choline-containing foods to their patients. Awareness, however, was even lower amongst obstetricians and gynaecologists, with only six per cent reporting that they would recommend choline-containing foods for a healthy pregnancy.8 This article sets out to discuss why choline may be beneficial for health in pregnancy, presenting evidence from latest research. Information about current intakes, dietary guidelines and how to integrate adequate amounts of choline-rich foods within the daily diet is also provided.
Choline
Polymorphisms in the PEMT gene mean that it is less responsive to estrogen and subsequently phosphatidylethanolamine will not be converted to phosphatidylcholine or choline as effectively.
Unfortunately, few studies have quantified how much choline is consumed in the UK. We therefore, need to look at data from other regions in order to ascertain ‘how much’ women are consuming. Data from the American Nurses’ Health Study recorded the dietary intakes of choline from a sample of 1477 women, aged 30-55 years. The median intake of choline was reported to be 323mg/day, with female, non-smoking exercisers generally having higher intakes of dietary folate, B vitamins and choline (>361mg choline/day).9
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Hot Topic | Choline A second study has been carried out on 62 medical students who completed three-day food diaries, from which choline intakes were quantified using the United States Department of Agriculture database. Mean choline intakes were not reported in this paper but 86per cent females (n=22) were found to have choline intakes that were lower than Institute of Medicine dietary guidelines, set at 425mg/day for non-pregnant females.10 Clearly larger, well-designed studies are needed, as well as more UK evidence. However, these papers give us some indication that choline intakes appear to fall short of dietary guidelines. Further studies are also now needed to measure choline status, alongside dietary intakes and account for the PEMT genetic polymorphism, which has generally not been considered.
Choline recommendations As present no UK recommendations for choline have been established. However, in the United States the Institute of Medicine categorised choline as an ‘essential micronutrient’ in 1998. Since then, Adequate Intakes, defined as the amount of a nutrient that is required to maintain health has been establish for different genders and age groups.11 These are summarised in Table One along with the tolerable upper intake (the highest level of intake studied with no side-effects reported) which is currently set at 3500mg/day for women of childbearing age.11 As can be seen in Table One, it is advised that non-pregnant women aim to consume 425mg choline per day, while pregnant and lactating mothers have marginally higher requirements set at 450mg and 550mg per day respectively.11 Interesting, choline requirements would probably be higher in pregnancy, but the rise in estrogen is thought to help support endogenous production in women without genetic polymorphisms.4
Food sources Choline may be present in foods as free choline, or in esterified forms (as phosphocholine, glycerophosphocholine, sphingomyelin and phosphatidylcholine). Of the esterified forms phosphatidylcholine is usually consumed in the highest quantities, as this is typical found in products of animal origin.3 As shown in Table Two a broad spectrum of foods contain choline and are suitable for consumption in pregnancy. In particular, animal products such as eggs (especially the yolk), lean meat and dairy foods are particularly rich sources.2 Some plant-based foods do contain choline, e.g. broccoli, brussel sprouts, cauliflower, and certain beans but levels per 100g are typically lower than amounts found in animal foods.12 Interestingly, lecithin (an emulsifying agent) is also a source of phosphatidylcholine and for this reason foods such as ice cream and mayonnaise can provide some choline.11 Turning to supplements, presently very few dietary supplements contain choline, placing
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greater emphasis on the need to consume this nutrient from dietary sources.12 Unfortunately, dietary restrictions that often come hand-in-hand with pregnancy e.g. guidance to avoid eating certain types of fish, e.g. shark, marlin and swordfish and limit the amount of tuna eaten to no more than two tuna steaks of four medium cans of tuna, avoid raw or partially cooked eggs or not eat cold meats13 may further limit choline intakes during this life phase.
Health in pregnancy
Table One: Dietary Reference Intake Values for Choline Life Phase and Guideline Adequate Intakes (AI)
Recommended Choline Intake (mg/day)
Females 14-18 years
400
Females ≥19 years
425
Pregnancy
450
Lactation
550
Tolerable Upper Limit (UL) Females 14-18 years
3000
Females ≥19 years
3500
Pregnancy
Age-appropriate UL
Lactation
Age-appropriate UL
Adequate intakes of choline in pregnancy are important because the foetus is unable to produce adequate phosphatidylcholine due to minimal or no PEMT being present within their liver.14 Consequently, maternal stores are utilised, with choline being transported across the placenta, carried within the amniotic fluid to the foetus.12 In fact, research has shown that the placenta contains 100mcmol/l choline compared to 20mcmol/l in the mother.14 Choline also plays a key role supporting the development of the nervous system15 and brain (particularly in the hippocampal region).16 There is some evidence suggesting that choline could play a role in reducing the risk of neural tube defects (NTDs). Work by Shaw et al. (2009) from Stanford School of Medicine has shown that NTDs still exist, even in areas of folic acid fortification, of when folic acid supplements are taken.17 Evidence from their prospective cohort study of pregnant women (n=180,000) showed that NTD risk was also highest amongst women with the lowest choline intakes (odds ratio 2.4 CI 1.3-4.7), compared with an odds ratio of 0.14 (CI 0.02-1.0) amongst women with the highest choline intakes.17 In an earlier case-control the same authors found some links between higher choline intakes and reduced risk of cleft lip,18 although further studies are needed to reinforce these findings. There is also some evidence suggesting that choline may help to reduce the risk of fetal alcohol spectrum disorder (FASD; mental and physical defects that can occur when a baby is exposed to alcohol). As previously mentioned, choline is an important methyl group donor and alcohol has been found to disturb the metabolism of methyl donors.4 A recent animal study examining the effects of alcohol exposure on hippocampal function using rats (some of which were injected with 100mg/kg choline chloride) found that alcohol exposure significantly affected hippocampal function, while choline went some way towards attenuating this.19
continued, choline levels increased, with serum and phospholipid-bound choline levels doubling around 12-28 days after birth (levels in colostrum were lower than amounts found in mature milk).20 It was concluded that this may could be an evolutionary mechanism to ensure that adequate supplies of choline are delivered to the foetus for continual brain development and growth of organs, i.e. kidney, liver, brain, lung and skeletal muscle early in infancy.20 Further studies of this nature are now needed to further reconfirm these findings.
Lactation
Discussion
Newborns’ have blood levels containing choline that are around three times higher than maternal blood levels. After birth choline is also present in human milk which may contain between 104 and 156mg choline per litre expressed.14 One study undertaken by IIcol et al. (2005) measured the choline status of women and their infants. It was found that as breast-feeding was
Presently, choline appears to be a nutrient that is overlooked, yet could have potential health benefits on pregnancy, especially for the developing foetus.21 Some evidence from preliminary studies indicates that choline intakes fall short of American dietary recommendations, especially when meat products are not eaten, or where there is a tendency to choose low-fat food options.4
Source: Institute of Medicine (2006)11
Table Two: Top Ten Choline-rich Rich Foods Suitable for Pregnancy Foods
mg per 100g
1. Egg, whole, cooked, hard boiled 2. Bacon (lean), pan-fried 3. Soybeans (mature seeds) 4. Ham (roasted) 5. Lean beef steak 6. Salmon 7. Cod 8. Chicken drumsticks 9. Flaxseeds 10. Quinoa
230 130 120 100 94 91 84 84 79 70
Note: Liver should not be consumed in pregnancy and if pregnant eggs should be cooked thoroughly. Source: Patterson et al. (2008)25
Choline | Hot Topic Other food aversions i.e. a dislike of fish may also further hamper choline intakes. For example, data from the UK National Diet and Nutrition Survey shows that adults aged 19-64 years only ate around 54g fish per week, the equivalent to around a third of the weekly recommendation.22 Restriction of fish consumption in pregnancy may also impact on choline intakes during this life phase. Current Scientific Advisory Committee on Nutrition advice is to eat no more than two portions per week, one of which should be oily fish. It is also recommended that certain fish species should be avoided due to concerns about fetal exposure to environmental contaminants.23 Daily choline intakes can be improved by making some simple dietary changes (Tables Three and Four for non-vegetarians and vegetarians), planning meals and eating a balanced diet containing a range of different foods.14 For example, the integration of eggs is one easy way to increase choline intakes. A review of scientific evidence has found that healthy adults may safely eat up to two eggs per day, to benefit from the range of nutrients (including choline in the yolk) that these can provide.24 Pregnant women, however, should ensure that these are cooked thoroughly - the egg and yolk should both be solid when eating, to reduce salmonella risk.13 Finally, as mentioned earlier in the article, a woman’s choline status may be further hampered by the fact that around 50 per cent premenopausal women have single nucleotide polymorphisms in the PEMT gene.2 This means that choline is not metabolised correctly and
dietary requirements in this population group are increased.24 This places a greater need for women to consume choline from dietary or supplement sources.4 Clearly, in the future better screening methods are needed to identify these individuals, so appropriate lifestyle adjustments can be made. Taking the findings from this review article on board, health professionals can play a key role in communicating the potential importance of choline to women in pregnancy. When advising expectant mothers on the use of pregnancy supplements, they should be advised to look for brands that contain choline. Otherwise, women should be advised to consume a balanced diet that contains plenty of choline-rich foods, as shown in Tables Three and Four. After birth, further studies are needed to reinforce preliminary findings but there do appear to be benefits associated with breastfeeding and mature milk being an important source of choline which is needed for infant brain development.
Conclusions In summary, choline is an important nutrient, needed both pre and postnatally. Health professionals can play a key role in encourage women to consume an array of choline-rich foods that are safe for ingestion in pregnancy and when breast feeding. Although further clinical evidence and randomised controlled trials are needed, preliminary research findings, as presented in this review look promising. It is anticipated that this is an area of work that we will hear much more of in the near future.
Acknowledgements: This review was kindly supported by Organix Foundation (www.organixfoundation.org/) whose employees played no role in the research or writing. The content reflects the opinions of the authors.
Key messages • Choline can be categorised as a B-vitamin and has wide-ranging roles in the human body • Presently intakes of choline generally appear to fall short of dietary guidelines, although more UK studies are needed • Simple dietary changes, e.g. regular egg consumption can help to top up dietary intakes of choline • Vegetarians and those that avoid meat/dairy consumption are most at risk of low choline intakes • More research is needed but choline may play a key role in supporting fetal development and preventing certain birth defects. References: 1. Strecker A (1862). Uber eingige neue bestandtheile der schweinegalle. Ann Chem Pharmacie; 183: 964–965. 2. Zeisel SH, et al. (2009). Choline: An Essential Nutrient for Public Health. Nutrition Reviews; 67: 11, 615-623. 3. Zeisel SH (2006). Choline: Critical Role During Fetal Development and Dietary Requirements in Adults. Annual Reviews of Nutrition; 26: 229-250. 4. Zeisel SH (2011). Nutritional Genomics: Defining the Dietary Requirement and Effects of Choline. Journal of Nutrition; 141: 531-534. 5. Derbyshire EJ (2007). Maternal nutrition and gene expression. British Journal of Nursing; 16: 13, 738-740. 6. Zeisel SH (2009). Importance of methyl donors during reproduction. The American Journal of Clinical Nutrition; 89: 2, 673S-677S. 7. Zeisel SH (2006). The fetal origins of memory: the role of dietary choline in optimal brain development. J Pediatr; 149(5 Suppl): S131-6. 8. Strategy One Health Professionals Survey (2007). Online study among 252 health care professionals from Harris Interactive Physicians and Specialty Health Professionals Panels. Sponsored by American Egg Board/Egg Nutrition Centre. Available at: http://www.cholineinfo.org/healthcare_pro fessionals/overview.asp (accessed March 2013). 9. Chiuve SE, et al (2007). The association between betaine and choline intakes and the plasma concentrations of homocysteine in women. American Journal of Clinical Nutrition; 86: 1073-1081. 10. Gossell-Williams M, Benjamin J (2006). Choline: Are our University Students Eating Enough? West Indian Medical Journal; 55: 3, 197-199. 11. Institute of Medicine (2006). Dietary Reference Intakes: The Essential Guide to Nutrient Requirements. The National Academies Press, Washington, DC. 12. Caudill MA, et al (2011). Elevating Awareness and Intake of Choline: An Essential Nutrient for Public Health. Nutrition Today; 46, 5: 235-241. 13. NHS Choices (2013). Foods to Avoid in Pregnancy. Available at: http://www.nhs.uk/conditions/pregnancy-andbaby/pages/foods-to-avoid-pregnant.aspx#close (accessed March 2013). 14. Caudill MA (2010). Pre- and Postnatal Health: Evidence of Increased Choline Needs. Journal of the American Dietetic Association; 110: 1198-1206. 15. Fischer LM, et al (2010). Dietary choline requirements of women: effects of estrogen and genetic variation. The American Journal of Clinical Nutrition; 92: 5, 1113-1119. 16. Zeisel SH, Niculescu MD (2006). Perinatal choline influences brain structure and function. Nutrition Reviews; 64: 4, 197-203. 17. Shaw GM, et al (2009). Choline and risk of neural tube defects in a folate-fortified population. Epidemiology; 20: 5, 714-9. 18. Shaw GM, et al (2006). Maternal nutrient intakes and risk of orofacial clefts. American Journal of Epidemiology; 17: 285-291. 19. Monk BR, et al (2012). The effects of perinatal choline supplementation on hippocampal cholinergic development in rats exposed to alcohol during the brain growth spurt. Hippocampus; 22: 8, 1750-7. 20. Ilcol YA et al (2005). Choline status in newborns, infants, children, breast-feeding women, breast-fed infants and human breast milk. Journal of Nutritional Biochemistry; 16: 489-499. 21. Derbyshire E (2011). Vitamins and pregnancy. In: Nutrition in the Childbearing Years. Oxford: Wiley Blackwell, pp137-38. 22. Bates B, et al (2012). National Diet and Nutrition Survey Headline Results from Years 1, 2 and 3 (combined) of the Rolling Programme (2008/2009-2010/11). London: Food Standards Agency/Department of Health. 23. Scientific Advisory Committee on Nutrition/Committee on Toxicity (SACN/CoT) (2004). Advice on Fish Consumption: Benefits and Risks. London: The Stationary Office. 24. Ruxton CHS, et al (2010). The nutritional properties and health benefits of eggs. Nutrition & Food Science; 40: 3, 263–279. 25. Patterson KY, et al (2008). USDA Database for the Choline Content of Common Foods: Release Two. U.S. Maryland: Department of Agriculture. Available at: http://www.nal.usda.gov/fnic/foodcomp/Data/Choline/Choln02.pdf (accessed March 2013). 26. U.S. Department of Agriculture (2012). National Nutrient Database for Standard Reference, Release 24. Maryland: Agricultural Research Service, National Agricultural Library.
Table Three: Meal Plan to Achieve 450mg Choline/day in Pregnancy Meal Plan Breakfast One medium bowl of Kellogg’s All Bran (40g) with a sliced banana (medium size) and Semi-skimmed milk Glass of fresh orange juice (200ml) 2 slices wholemeal toast spread thinly with butter Lunch Wholemeal baguette 2 slices of ham Side salad – lettuce, cucumber and tomato 1 hard-boiled egg, sliced Evening meal Chicken breast, skinless (170g) Cauliflower (75g) Peas (75g) Potatoes, mashed (100g) Apple pie, one average slice (65g) Snacks A large handful of grapes (around 20) Low fat fruit yogurt Kiwifruit x 2 Total
Choline Content (mg) 19.6 9 18 12 11
4.5 36.3 6.3 155 105 29 21 14 4.7 8.6 30 11 495
Source: Patterson et al. (2008); UDSA (2012)25,26.
Table Four: Meal Plan to Achieve 450mg Choline/day (for vegetarians) Vegetarian Meal Plan Breakfast Quaker Oats with honey and raisins (80g) Soy milk Decaffeinated coffee made with water and skimmed milk
Choline Content (mg) 25.6 30 16
Blueberry muffin, small Lunch Tomato Soup with grated cheese Grated cheddar cheese (10g) Wholemeal bread roll Evening meal Quinoa (150g) and edamame (green soybean) salad
16
Edamame (100g) Onion (quarter) Juice of one lemon Vanilla ice cream 7 strawberries Snacks Hot chocolate made with milk Tangerine x 2 Chocolate chip granola bar Cream cheese Handful of flaxseeds (30g) Total
56 1.6 0.4 17.2 5
52 1.7 8.1 105
42 14 7.6 20 24 442
Source: Patterson et al. (2008); USDA (2012).25, 26
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