One of my goals for this blog is to bring attention to the variety of essential nutrients that we “Paleo kids” need to make sure we’re getting in our diet. One of the major problems with the mainstream understanding of Paleo eating is the lack of attention to micronutrient content of our food. Part of this problem comes from applying Paleo principles to old habits from the standard American diet. A newbie  to the Paleo/Primal/Ancestral lifestyle may think that cutting out grains and processed dairy is enough to be healthy. It’s a start, of course, but certainly not the end goal. Liz from Cave Girl Eats and I discussed the importance of including nutrient dense foods as part of a Paleo/Primal lifestyle, and we both agreed that many people would benefit from learning the importance of particular nutrients.

So as often as I can, I’m going to write informative articles about specific nutrients that tend to be lacking from everyone’s diets (myself included). I will bring up the role of each nutrient in the body, deficiency symptoms, lifestyle factors that may cause deficiencies, and Paleo-approved ways to get the nutrients back into your diet through highly nutrient-dense foods. I’m coming at this from an “RD-in-training” perspective, so my continuing education at UNC will inform many of my posts, as well as consultations with experts such as Chris Masterjohn, and (don’t laugh) my mother, Pamela Schoenfeld, who is a private practice RD, the unofficial “official” RD for the Weston A. Price Foundation, and my personal guru when it comes to nutritional accuracy. She’s kind of a big deal.

For my first article regarding micronutrients, I cheated a little and decided to post a paper I wrote for one of my classes. The nutrient I focused on was choline, and the population target is women of childbearing age. Interestingly, I think many of my friends tend to forget that even though most of us are more concerned with NOT getting pregnant, that our nutritional status is a vital component of our future fertility, and we should be thinking about taking some precaution now to ensure that when we finally are ready to get pregnant, that we’ll be successful and our children will be healthy. Considering that infertility affects about 12 percent of the child-bearing female population, and about 1 in 8 couples, (according to the CDC), and that birth defects and birth disorders affect over 150,000 children every year in America, I think its important that young women start considering their future family planning now, and not wait until they’ve gotten a positive pregnancy test to start popping synthetic prenatal vitamins to try and play catch-up.

If you’re interested in learning more about why choline is such an essential nutrient for healthy pregnancy outcomes, please read the following (sort of long) paper.

Take home message to all you “Cave Girls” out there – EAT THE DAMN EGG YOLK!!! 🙂

Cholesterol Intake, Choline Deficiency, and Birth Outcomes

Recommendations for Practice

Introduction to Choline

Choline has been established by the Institute of Medicine as a vital nutrient needed at a certain intake level for all people, including pregnant and lactating women. While the body is capable of biosynthesizing some amount of choline, this organic compound is required in small amounts in the diet to maintain normal health for all individuals (1). Choline plays a myriad of roles in the body’s metabolism: the synthesis of the neurotransmitter acetylcholine, cell-membrane signaling, lipid transport, and methyl-group metabolism (2). In addition, it is an essential component of the many phospholipids that make up cell membranes, regulates several metabolic pathways, and aids detoxification in the body (2). During pregnancy, it is directly related to brain and memory development in the fetus and can influence the risk of the development of neural tube defects (2). Choline clearly plays a significant role in a variety of essential metabolic activities and developmental outcomes, and researchers continue to discover new functions in the human body for this vital compound.

The Issue of Perinatal Dietary Choline Intake

Despite its importance, choline has only been recognized as an essential nutrient since 1998, when the Food and Nutrition Board of the Institute of Medicine established an Adequate Intake (AI) level of 425 mg per day for women and 550 mg per day for men (2). The Institute of Medicine also recognized that the need for choline increases during pregnancy and lactation, and established AI levels of 450 and 550 mg per day for these life stages, respectively (2). However, many Americans are not familiar with choline as an essential nutrient, and often do not consider whether their diet is supplying enough to meet these AI recommendations (2). It has been established that the majority of Americans, and pregnant American women in particular, do not consume adequate levels of choline in their diet (3), even though there are many dietary sources of the nutrient.

The FDA defines an “excellent” source of choline as one that has 110 mg or more per serving, satisfying 20% of the 550 mg daily value reference, while a “good” source is 55 mg per serving (4). Many of the foods that are categorized as excellent sources of bioavailable choline, such as beef liver, poultry liver, and whole eggs, are also very high in cholesterol. For example, according to the USDA, one whole egg contains approximately 140 mg of choline (5), satisfying approximately one quarter of a pregnant woman’s daily requirements for choline. However, one whole egg also contains 208 mg of cholesterol (6), which is approximately two-thirds of the 300 mg maximum intake for all adults as recommended by the USDA (7). Beef liver, which has 355 mg of choline in a three ounce serving, contains 337 mg of cholesterol (6), which is well over the 300 mg recommendations. There are a few plant foods that contain moderate amounts of choline, such as brussels sprouts (40.7 mg choline/100g), cauliflower (39.1 mg choline/100g), and various nuts such as pistachios (71.5 mg choline/100g) and cashews (61 mg choline/100g) (5). However, these are notably lower choline values than animal foods such as eggs (251.0 mg choline/100g) or beef liver (426.1 mg choline/100g). In fact, most of the top sources of choline as ranked by the USDA are animal products that are high in cholesterol (5), which therefore raises the following question: should clinicians be advising pregnant or lactating women to adhere to the USDA guidelines for cholesterol intake if adherence may consequently reduce these women’s dietary choline intake?

Literature Review on the Effects of Choline During Pregnancy

To answer the previous question, one must consider the effects of dietary choline intake on choline status of pregnant and lactating women, and especially how these levels affect the choline status and subsequent physical development of their children. First, it is important to understand what direct effects measured choline deficiency has on the outcome of a pregnancy. While this type of study is unethical to perform in human subjects, many animal studies have been designed to explore the effect of limiting choline availability in the diet of a pregnant rat or mouse and studying its offspring. Several studies have been conducted over the past few decades demonstrating that maternal choline deficiency during pregnancy alters neurogenesis and increases cell apoptosis in the fetal mouse hippocampus, which can lead to significantly decreased visuospatial and auditory memory in adulthood (2,8,9).

Many choline deficiency studies have focused on the effects of choline deficiency on fetal brain development in animals. Mehedint and his colleagues sought to determine the effect of deficient maternal choline intake on fetal angiogenesis in the hippocampus of fetal mice, a developmental process that ensures that neurons are supplied with oxygen and that waste products are removed from the brain (8). To determine the angiogenic outcomes in the fetal brains, pregnant mice were fed choline deficient, control, or choline supplemented diets between days 12 to 17 of gestation, and fetal brains were collected on day 17 of gestation. In the choline deficient fetal hippocampus, proliferation of endothelial cells was decreased by 32% compared to the control and choline supplemented diets, which led to a 25% decrease in the number of blood vessels in that area of the brain. This decreased angiogenesis can lead to impaired brain development due to poor oxygen delivery or inadequate waste removal (8), and may lead to significant learning and memory impairment later in life.

Choline deficiency has been demonstrated to significantly affect more than just brain development in the growing mouse fetus, and effects can be seen in other major organs such as the heart. Chan and her colleagues studied the effects of low dietary choline on embryonic growth and cardiac development in mice (10). This was one of the first animal studies on choline deficient pregnancies to focus on heart development rather than brain development in fetal mice. Female mice were fed either a control diet or a choline deficient diet from 6 weeks prior to coitum until 14.5 days post-coitum. The researchers then collected embryos from these mice and examined their developmental outcomes. There were significantly more heart defects, specifically ventricular septal defects, in embryos from the choline deficient diet fed females than from the control diet fed females. These results suggest that choline deficiency may affect cardiac structure (10), and that choline deficiency can increase the risk of congenital heart defects.

While the limitations of these various animal studies are primarily that these results were demonstrated in rodents and not in humans, the results can reasonably be generalized to human fetal development, demonstrating the need for adequate choline availability during pregnancy. Since, according to NHANES data, only 14% of pregnant women in the United States consume adequate amounts of choline in their diets (8), these studies suggest that many of these women’s offspring may be at a higher risk for underdeveloped brain growth or impaired cardiac development. Furthermore, these results suggest that ensuring adequate choline availability may also play a role in preventing these types of pregnancy complications in women.

To demonstrate the importance of adequate dietary choline intake on choline availability during a pregnancy, Fischer and her colleagues sought to determine how choline intake affects concentrations of choline in the blood and breast milk of pregnant and lactating women (11). The researchers enrolled 108 healthy pregnant women at 18 weeks gestation, of which one-half of the participants were randomly assigned to be given a choline supplement that provided 750 mg of choline per day, in the form of phosphatidylcholine, from 18 weeks of pregnancy through 90 days postpartum. The other half of the participants received a placebo supplement. All participants were also asked to keep a complete a three-day food record representative of their usual intake to analyze their daily intake of dietary choline. It was determined that of the 108 participants studied, only 5 participants consumed a level at or above the AI of 550 mg per day for pregnant women.

The researchers analyzed the blood and breast milk samples to determine how the participants’ choline intakes affected their choline status. Those taking the phosphatidylcholine supplement had significantly higher concentrations of free choline in their plasma relative to those in the placebo group irrespective of dietary intake. In all subjects combined, breast milk concentrations of choline were positively correlated with the total intake of choline in the diet plus the supplement. Dietary choline was also directly correlated with plasma choline concentrations. The researchers concluded that blood and breast milk concentrations of choline can be significantly influenced by diet and dietary supplements. This is especially important because the researchers noticed that the participants’ dietary intake of choline was low relative to the recommended AI for pregnant and lactating women, since only 5 of the 108 subjects consumed diets that met or exceeded the AI for choline. This research is important for two reasons. First, it demonstrated that dietary choline levels significantly affect both maternal plasma levels of choline as well as choline levels in the breast milk of lactating women. Since choline has been demonstrated to be essential for the growth and development of brain and major organs in the fetus as well as the neonate (11), adequate maternal supplies during gestation and lactation should be achieved through increasing dietary and/or supplemental intake. Second, this study demonstrated that over 95% of the participants did not consume the recommended AI levels of choline, which would suggest that many of these pregnant women had inadequate dietary intakes of choline.

The results of this study were fairly well supported, yet there were some limitations noted by the authors. All patients took prenatal vitamins with folic acid, which may have obscured some of the effects of choline supplementation due to possible intersection in the pathways of folate and choline metabolism (12). The relatively small sample size used may have limited the scope of the results, and a larger, more diverse population should be studied in the future. However, despite these possible limitations, this study demonstrates that choline intake directly affects serum and breast milk levels of choline of pregnant and lactating women.

While it has been determined that poor dietary intake of choline reduces maternal stores, and that deficient intake in mice and rats can lead to serious complications in fetal rain and heart development, it is important to demonstrate the effects of choline deficiency in human birth outcomes. In 2004, Shaw and his colleagues sought to determine if dietary intakes of choline were associated with the risk for neural tube defects (NTDs) in humans (13). The authors examined a large population-based case-control study to investigate the association between choline intake and NTD-affected pregnancies. Controls without reportable congenital anomalies were randomly selected, and in total, 864 women were assessed. 424 were mothers of NTD cases and 440 were mothers of controls. The 424 cases included 161 with anencephaly, 242 with spina bifida, and 21 with other NTD phenotypes. Each woman in the cohort was given a standard, validated 100-item food frequency questionnaire to assess nutrient intake from their diet during the 3 months before conception. Choline values were assigned using nutrient values from the NHANES food consumption values, and assessors of diet were blind to case status. Data regarding folate intake was also compiled to control for the effects of folate and folic acid supplementation.

When the researchers compared the diets of the women in the cohort, the risk of NTD-affected pregnancies were decreased following higher periconceptional intakes of choline for all NTDs, as well as for spina bifida and anencephaly separately. After controlling for intake of supplemental folic acid, dietary folate, dietary methionine, and other covariates, there was no substantial influence on these risk estimates for choline. Overall, NTD risk estimates were lowest for women whose diets were rich in choline, irrespective of folate intake.

This study, while drawing from a large sample size and controlling for many variables, is limited in the sense that it did not measure tissue concentrations of choline in the maternal subjects, and therefore differences in choline status may have been attributable to recall bias for foods typically higher or lower in choline (13). Issues in recall may have affected data on subjects’ dietary intakes, since the food frequency questionnaires were given several months following the completion of pregnancy (an average of 4.9 months for cases and 4.6 months for controls after the actual or projected date of term delivery). Future research would benefit from testing blood or breast milk levels of choline in women with both healthy and NTD-affected pregnancies. Despite these shortcomings, however, this study provides strong evidence for the existence of an association between dietary choline intake and risk of neural tube defects in a pregnancy, regardless of folate intake. Considering that most women are not counseled about their choline intake, this finding can have serious implications for public health guidelines for diet during pregnancy and lactation.

It has been established through research that choline intake needs significantly increase during pregnancy and lactation, since large amounts of choline are both supplied to fetus across the placenta (14), as well as secreted in a mother’s milk (11,15); these requirements can deplete maternal stores of choline, demonstrating the need to increase dietary intake at these times (9,11). As it has been previously stated, the majority of women in the United States do not consume the adequate intake (AI) levels of choline, particularly during pregnancy (3). Furthermore, most prenatal supplements and multivitamins generally do not contain choline (16), and therefore for most pregnant women, their exogenous choline comes from dietary sources alone.

Issues Facing Clinical Guidelines and Public Health Intervention

Clinicians are therefore faced with a challenge in their dietary recommendations to pregnant clients. It would seem intuitive, based on the aforementioned research, to suggest that pregnant women try to include a wide variety of choline rich foods in their perinatal diets. It has been established that many of the best sources of choline for pregnant women are from animal foods that are very high in cholesterol, such as eggs or liver. It has also been established that dietary cholesterol is currently recommended at an intake below 300 mg per day for all people, and below 200 mg for those with risk factors for heart disease (7). However, since it has been demonstrated in a wide variety of studies that adequate dietary choline is essential for a healthy pregnancy outcome, it seems that clinical dietary recommendations for limiting cholesterol should, at a minimum, be modified for healthy women of childbearing age, and especially those healthy women who are pregnant or lactating. Furthermore, considering most of the best sources of choline come from animal foods, supporting dietary habits such as strict vegetarianism or veganism and complete avoidance of animal foods may not be advisable during pregnancy and lactation. At the very least, choline supplementation should be recommended for women who may be at higher risk choline deficiency due to certain diet restrictions. However, choline supplementation may be problematic for women of low socioeconomic status due to cost, since choline supplements are not currently provided to participants of government services such as the WIC (Women, Infants, Children) program, and choline is not routinely added to prenatal vitamins (16).

It is clear from the data that choline is an essential nutrient for human health, and it is particularly necessary for a healthy pregnancy. It is also evident from epidemiological studies that the majority of women in the United States do not consume adequate levels of choline in their perinatal diets, and that typical prenatal supplements do not generally provide choline. Finally, it is also apparent that the most abundant sources of dietary choline come from animal products that are also high in cholesterol. What is not clear, however, is the most appropriate next step to take from a public health standpoint. If cholesterol recommendations were modified for healthy women of childbearing age, it would possibly be easier for these women to get adequate intake of choline in their diet from high cholesterol foods like eggs, liver, beef, and milk, which are good or excellent sources of dietary choline, among other essential nutrients. Another option is to reformulate prenatal vitamins to include a significant amount of choline, thereby helping women to increase their choline intake without modifying their diet, and allowing low-income women to receive choline supplementation when provided with prenatal vitamins from the WIC program. Regardless of how women are encouraged to increase their choline intake during pregnancy, it is essential that public health officials and clinicians recognize the importance of choline in pregnant and lactating women’s diets, and take the necessary steps to ensure that their patients are meeting their adequate daily intake levels of this vital, and often overlooked, nutrient.

References

1. Blusztajn JK. Choline, a vital amine. Science. 1998;281:794.
2. Ziesel, SH, da Costa, KA. Choline: An Essential Nutrient for Public Health. Nutr Rev. 2009;67:615–623.
3. Jensen HH, Batres-Marquez SP, Carriquiry A, Schalinske KL. Choline in the diets of the US population: NHANES, 2003-2004. FASEB J. 2007;21:lb219.
4. FDA. Nutrient Content Claims Notification for Choline Containing Foods. http://www.fda.gov/Food/LabelingNutrition/LabelClaims/FDAModernizationActFDAMAClaims/ucm073599.htm
5. Patterson KY, Bhagwat SA, Williams JR, Howe JC, Holden JM. USDA database for the choline content of common foods, release two. USDA Agricultural Research Service. 2008.
6. U.S. Department of Agriculture, Agricultural Research Service. 2010. USDA National Nutrient Database for Standard Reference, Release 23. Nutrient Data Laboratory Home Page, http://www.ars.usda.gov/nutrientdata
7. U.S. Department of Agriculture and U.S. Department of Health and Human Services. Dietary Guidelines for Americans, 2010. 7th Edition, Washington, DC: U.S. Government Printing Office, December 2010.
8. Mihai G. Mehedint, Corneliu N. Craciunescu, & Zeisel, SH. Maternal dietary choline deficiency alters angiogenesis in fetal mouse hippocampus. Proc Natl Acad Sci USA. 2010;107:12834-9.
9. Zeisel SH. Choline: Needed for Normal Development of Memory. J Am Coll Nutr. 2000;19:528S-531S.
10. Chan J, Deng L, Mikael LG, et al. Low dietary choline and low dietary riboflavin during pregnancy influence reproductive outcomes and heart development in mice, Am J Clin Nutr. 2010;91:1035-43.
11. Fischer LM, da Costa KA, Galanko J, Sha W, Stephenson B, Vick J, Zeisel SH. Choline intake and genetic polymorphisms influence choline metabolite concentrations in human breast milk and plasma. Am J Clin Nutr. 2010;92:336-46.
12. Craciunescu CN, Johnson AR, Zeisel SH. Dietary Choline Reverses Some, but Not All, Effects of Folate Deficiency on Neurogenesis and Apoptosis in Fetal Mouse Brain. J Nutr. 2010;140(Jensen):1162-6.
13. 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.
14. Welsch F: Studies on accumulation and metabolic fate of (N- Me3H)choline in human term placenta fragments. Biochem. Pharmacol. 1976;25:1021–1030,.
15. Holmes-McNary M, Cheng WL, Mar MH, Fussell S, Zeisel SH: Choline and choline esters in human and rat milk and infant formulas. Am J Clin Nutr. 1996;64:572–576.
16. Caudill MA. 2010. Pre- and Postnatal Health: Evidence of Increased Choline Needs. J Am Diet Assoc. 2010;110:1198-1206.

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