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Suggested Citation:"3 One-Carbon Metabolism Micronutrients." National Academies of Sciences, Engineering, and Medicine. 2020. Nutrition During Pregnancy and Lactation: Exploring New Evidence: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/25841.
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Suggested Citation:"3 One-Carbon Metabolism Micronutrients." National Academies of Sciences, Engineering, and Medicine. 2020. Nutrition During Pregnancy and Lactation: Exploring New Evidence: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/25841.
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Suggested Citation:"3 One-Carbon Metabolism Micronutrients." National Academies of Sciences, Engineering, and Medicine. 2020. Nutrition During Pregnancy and Lactation: Exploring New Evidence: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/25841.
×
Page 27
Suggested Citation:"3 One-Carbon Metabolism Micronutrients." National Academies of Sciences, Engineering, and Medicine. 2020. Nutrition During Pregnancy and Lactation: Exploring New Evidence: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/25841.
×
Page 28
Suggested Citation:"3 One-Carbon Metabolism Micronutrients." National Academies of Sciences, Engineering, and Medicine. 2020. Nutrition During Pregnancy and Lactation: Exploring New Evidence: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/25841.
×
Page 29
Suggested Citation:"3 One-Carbon Metabolism Micronutrients." National Academies of Sciences, Engineering, and Medicine. 2020. Nutrition During Pregnancy and Lactation: Exploring New Evidence: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/25841.
×
Page 30
Suggested Citation:"3 One-Carbon Metabolism Micronutrients." National Academies of Sciences, Engineering, and Medicine. 2020. Nutrition During Pregnancy and Lactation: Exploring New Evidence: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/25841.
×
Page 31
Suggested Citation:"3 One-Carbon Metabolism Micronutrients." National Academies of Sciences, Engineering, and Medicine. 2020. Nutrition During Pregnancy and Lactation: Exploring New Evidence: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/25841.
×
Page 32
Suggested Citation:"3 One-Carbon Metabolism Micronutrients." National Academies of Sciences, Engineering, and Medicine. 2020. Nutrition During Pregnancy and Lactation: Exploring New Evidence: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/25841.
×
Page 33
Suggested Citation:"3 One-Carbon Metabolism Micronutrients." National Academies of Sciences, Engineering, and Medicine. 2020. Nutrition During Pregnancy and Lactation: Exploring New Evidence: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/25841.
×
Page 34
Suggested Citation:"3 One-Carbon Metabolism Micronutrients." National Academies of Sciences, Engineering, and Medicine. 2020. Nutrition During Pregnancy and Lactation: Exploring New Evidence: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/25841.
×
Page 35
Suggested Citation:"3 One-Carbon Metabolism Micronutrients." National Academies of Sciences, Engineering, and Medicine. 2020. Nutrition During Pregnancy and Lactation: Exploring New Evidence: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/25841.
×
Page 36
Suggested Citation:"3 One-Carbon Metabolism Micronutrients." National Academies of Sciences, Engineering, and Medicine. 2020. Nutrition During Pregnancy and Lactation: Exploring New Evidence: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/25841.
×
Page 37
Suggested Citation:"3 One-Carbon Metabolism Micronutrients." National Academies of Sciences, Engineering, and Medicine. 2020. Nutrition During Pregnancy and Lactation: Exploring New Evidence: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/25841.
×
Page 38

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3 One-Carbon Metabolism Micronutrients Micronutrients involved in one-carbon metabolism1 are critical to both maternal health and fetal development. Deficiencies of these nutrients have been linked to adverse pregnancy outcomes such as congenital birth defects, fetal growth disorders, and preterm birth. Over the past several decades, intakes of one-carbon metabolism nutrients has changed. Folic acid fortifi- cation, for instance, makes the nutrient more pervasive in the food supply. While intake of certain one-carbon metabolism nutrients (e.g., synthetic folic acid) may be high in some subpopulation groups, intake of others (e.g., vitamin B12, choline) may be inadequate. The second session of the workshop, moderated by Tamera Hatfield, a maternal–fetal medicine spe- cialist on faculty at the University of California, Irvine, reviewed evidence that has emerged on the roles and need for folate, folic acid, vitamin B12, and choline during pregnancy and lactation, and explored the potential misalignment of current recommendations with current intakes. Highlights from the session presentations are presented in Box 3-1. DISCREPANCIES IN FOLATE AND VITAMIN B12 STATUS OF PREGNANT WOMEN ACROSS POPULATION GROUPS AND THE POSSIBLE IMPLICATIONS FOR CHILD OUTCOMES In her remarks, Yvonne Lamers, associate professor in the Food Nutri- tion and Health Program at The University of British Columbia, provided 1  One-carbon metabolism encompasses interrelated biochemical reactions that involves the transfer of 1-carbon units (methyl groups). These reactions play key roles in various physi- ological processes. 25 PREPUBLICATION COPY—Uncorrected Proofs

26 NUTRITION DURING PREGNANCY AND LACTATION BOX 3-1 Highlights from the Session 2 Presentations • Despite folic acid fortification, intake data indicate folic acid supplementation is still necessary for women of reproductive age to meet folate needs (Lamers). • About 20 percent of women of reproductive age have red blood cell folate concentrations below the cutoff for optimal neural tube defect prevention (Lamers). • A sizeable percentage of pregnant women who use supplements have a total intake of folic acid (the form recommended for the prevention of neural tube defects) above the recommended dose of 400 mg/day and above the Tolerable Upper Intake Level, suggesting a need to better align supplement content with current recommendations (Lamers). • Although dietary data suggest vitamin B12 intakes of pregnant women are adequate across trimesters, evidence suggests a decrease in vitamin B12 biomarker concentrations over the course of pregnancy (Lamers). • Pregnancy-specific cutoffs for vitamin B12 biomarkers validated with physi- ologic outcomes are needed (Lamers). • Fetal and infant development require large amounts of choline (Caudill). • Evidence suggests that higher maternal choline intake likely improves preg- nancy outcomes and offspring neurocognitive health (Caudill). • Most pregnant women are consuming less than the choline Adequate Intake (Caudill). NOTE: These points were made by the individual workshop speakers identified above. They are not intended to reflect a consensus among workshop par- ticipants. The statements have not been endorsed or verified by the National A ­ cademies of Sciences, Engineering, and Medicine. an overview of the evidence that has emerged over the past several decades related to the roles and intake of folate, folic acid, and vitamin B12 during pregnancy. In addition to discussing the use of supplements and the status of pregnant women related to these nutrients, Lamers also identified open questions and knowledge gaps that currently exist. Folic Acid Supplementation and Fortification One of the biggest milestones in maternal nutrition that has taken place over the past 30 years is the recognition that periconceptional folic acid can prevent neural tube defects, said Lamers. First released in the early 1990s, recommendations for preconceptual folic acid supplementation were driven by results from two randomized controlled trials that found supple- menting low-risk women reduced the incidence of neural tube defects by PREPUBLICATION COPY—Uncorrected Proofs

ONE-CARBON METABOLISM MICRONUTRIENTS 27 at least 90 percent (Berry et al., 1999; Czeizel, 2009). Current guidelines generally recommend that women of reproductive age who have a low risk of giving birth to a baby with neural tube defects take a 400 μg/day folic acid supplement at least 1 month prior to conception through 12 weeks gestation. However, there are some variations in recommendations interna- tionally, noted Lamers. For instance, the New Zealand Ministry of Health recommends an 800 μg/day dose of folic acid and the Canadian Society of Obstetricians and Gynecologists recommends that supplementation con- tinues at least until 1 month postpartum or until the end of breastfeeding. Despite recommendations, the prevalence of folic acid supplement use tends to be low. Estimates of preconceptual folic acid supplementation use in the United States and Canada range from 14 to 60 percent (Bailey et al., 2019; Chalmers et al., 2008; Masih et al., 2015) and 12 to 20 per- cent in Europe (McNulty et al., 2011; Nilsen et al., 2006). Women with planned pregnancies are more likely to be using folic acid supplements at pre­ onception (Masih et al., 2015; Nilsen et al., 2006); however, approxi- c mately 45 percent of pregnancies in the United States are unplanned (Finer and Zolna, 2016), observed Lamers. Folic acid fortification is a population-based strategy used to prevent neural tube defects. Mandatory folic acid fortification of foods (e.g., wheat flour, maize flour, rice) has been implemented in 71 countries. Mandatory folic acid fortification in the United States and Canada has been esti- mated to decrease neural tube defects by 31 and 46 percent, respectively (De Wals et al., 2007; Williams et al., 2002). Lamers commented that some countries—including New Zealand, the United Kingdom, and other ­ European countries—have not adopted mandatory folic acid fortification p ­ rograms owing to safety concerns. Folate Status and Intake of Pregnant Women Red blood cell (RBC) folate concentration is used to monitor folic acid supplementation programs. The World Health Organization (WHO) uses an RBC folate concentration of 906 nmol/L as a threshold for sufficiency and optimal neural tube defect prevention (Cordero et al., 2015). Approxi- mately 20 percent of women in both the United States (Pfeiffer et al., 2019) and Canada (Colapinto et al., 2011) have RBC folate concentrations below this threshold, stated Lamers. She showed that although there are no dif- ferences by age groups, the prevalence of RBC folate concentrations falling below the WHO threshold tends to be higher among African American women and women who do not use supplements (Pfeiffer et al., 2019). Intakes of dietary folate and folic acid reveals both inadequate and possibly excessive intakes in the population. Describing a recent analysis of National Health and Nutrition Examination Survey (NHANES) data PREPUBLICATION COPY—Uncorrected Proofs

28 NUTRITION DURING PREGNANCY AND LACTATION (­ ailey et al., 2019), Lamers noted that 16 percent of all pregnant women B in the United States have total dietary folate intakes below the Estimated Average Requirement (EAR), indicative of inadequacy. This finding sug- gests that, despite the folic acid fortification efforts in the United States, supplements are still needed. However, the NHANES analysis also revealed that 48 percent of pregnant supplement users exceed the Tolerable Upper Intake Level (UL) for folic acid of 1,000 μg/day. These excessive intakes are attributed to supplement use, rather than fortified food sources, said Lamers. Explaining that similar findings have been reported in Canada, she remarked that prenatal supplements often contain 800–1,000 μg folic acid and that Canadian women are encouraged to continue supplemen- tation throughout the duration of their pregnancy. Lamers pointed to a recent workshop (Lamers et al., 2018) that explored the current state of inadequate and excessive folic acid intake as an impetus to align folic acid content in prenatal supplements to the current recommendations of 400 μg/day folic acid. Birth and Child Developmental Outcomes Related to Prenatal Folic Acid Intake Studies have investigated relationships between prenatal folic acid intake and a variety of birth and developmental outcomes. There appears to be no association between folic acid supplementation and birth weight, risk of preterm birth, or stillbirths and neonatal deaths (Lassi et al., 2013). Lamers explained that there is no association between folic acid intake in the first trimester and risk of asthma in children, but the evidence for a relationship in the second and third trimesters are conflicting (Crider et al., 2013). There are inconsistent relationships with risk of autism, obesity, and insulin resistance in the offspring (Gao et al., 2016; Xie et al., 2016). In exploring the relationships between outcomes and high folic acid intakes, Lamers cautioned that there are important limitations to consider. She noted that relationships reported in the literature are associations and face issues of biases and confounding. Furthermore, there is no standard definition for what constitutes high or excessive folic acid intake, and the available evidence does not lend itself to determining dose–response rela- tionships. Lamers described the existing evidence on these relationships as inconsistent and equivocal. She put forth the concept of the precautionary principle in the face of scientific uncertainty, which she captured by saying “400 micrograms was shown to be effective in lowering neural tube defects, so why more?” It is biologically plausible that folate, as a key methyl donor, leads to epigenetic alterations (e.g., DNA methylation, histone modification) and changes to gene expression, suggested Lamers. She continued, stating that PREPUBLICATION COPY—Uncorrected Proofs

ONE-CARBON METABOLISM MICRONUTRIENTS 29 given the developmental origins of health and disease theory, it is possible that folate plays a role in disease outcomes. In addition to its role in the closure of the neural tube in the first weeks of pregnancy, folate is a key nutrient for brain function. Observational s ­ tudies have reported either positive or no associations between maternal folate status in early or late pregnancy and child behavioral outcomes, reported Lamers. Two randomized trials have been conducted to further explore this relationship. A multicenter, randomized controlled trial used a two-by-two factorial design to assess the effects of 400 μg/day of natural folate called 5-methyltetrahydrofolate (5-MTHF), fish oil, and placebo during the second half of pregnancy. Children of women who received the 5-MTHF supplement showed higher executive function at 8.5 years of age (Catena et al., 2016). Another trial, conducted in Northern Ireland, randomized 119 women to receive either 400 μg/day folic acid or placebo during the second and third trimesters of their pregnancies. At 7 years of age, children of the women who received the folic acid supplement had improved developmental outcomes (McNulty et al., 2019). Investigators also found significantly lower DNA methylation of genes related to brain development in the cord blood of neonates born to women who continued folic acid supplementation in their second and third trimesters (Caffrey et al., 2018). “Whether those epigenetic alterations are related to the brain outcome status has not been looked at yet. These data have just been recently released,” advised Lamers. Research Needs Related to Folate and Folic Acid Lamers highlighted three key questions that have emerged since the release of the periconceptional folic acid supplementation recommendations in the early 1990s. First, she stated that a need exists to identify women who are at risk for insufficient folate intake. For some women, the barrier may be a matter of access. As evidenced by the 20 percent of reproductive- aged women with RBC folate below the WHO threshold for sufficiency, which was independent of socioeconomic status, another barrier may be knowledge transfer, suggested Lamers. She also thought that changes in dietary patterns in the population (e.g., promotion of plant-based diets and avoidance of gluten-containing foods) merit monitoring of folic acid and folate intake. Second, questions have been raised as to whether more folate or folic acid is needed among women who have the methylenetetra- hydrofolate reductase (MTHFR) 677C>T genetic variant. Third, Lamers emphasized the need for trimester-specific, dose–response studies to assess the effects of prolonged folic acid supplementation. PREPUBLICATION COPY—Uncorrected Proofs

30 NUTRITION DURING PREGNANCY AND LACTATION Vitamin B12 Needs and Status During Pregnancy Lamers showed the Dietary Reference Intake values that have been established for adequate vitamin B12 intake among women. For women of reproductive age, the Estimated Average Requirement (EAR) and Recom- mended Dietary Allowance (RDA) are set at 2.0 and 2.4 μg/day, respec- tively, based on hematologic indicators. The values for pregnant women increase to 2.2 μg/day for the EAR and 2.6 μg/day for the RDA, to account for fetal deposition and increases in absorption, and further increase to 2.3 and 2.8 μg/day, respectively, for lactating women. Vitamin B12 is found in animal sources and fortified foods, noted ­ amers. L Given this, there are various population groups at risk for inadequate B12 ­ intake, including certain ethnic groups and those who follow dietary pat- terns that limit or exclude animal sources (e.g., vegetarian, vegan). Studies of vitamin B12 intake using dietary data indicate that women across trimesters of pregnancy are consuming above the levels recommended for adequacy (Blumfield et al., 2013), with median intake estimated to be approximately 5 μg/day in supplemented women (Wu et al., 2013). Lamers contrasted the vitamin B12 dietary intake findings with bio- marker data. Over the course of pregnancy, total B12 concentrations decrease (­ chroder et al., 2017; Visentin et al., 2016), likely owing to hemo­ ilution S d and other pregnancy-related physiologic changes, said Lamers. She suggested ­ recently derived pregnancy-specific cutoffs for vitamin B12 bio­ arkersm (­ chroder et al., 2019) should be validated. To validate such work, the rela- S tionship between low vitamin B12 status and a host of perinatal outcomes has been evaluated (e.g., low birth weight, preterm birth, small-for-gestational age). From this work, it has been estimated that 34 percent of neural tube defects in Canada may be related to low vitamin B12 status, reported Lamers. Adequate Intakes of vitamin B12 during pregnancy may have impli- cations not only for birth outcomes but also for the infant’s vitamin B12 status. Fetal vitamin B12 stores develop in utero. Evidence suggests that at 12 months of age, an infant’s vitamin B12 status is associated with mater- nal serum vitamin B12 status during pregnancy, rather than breast milk concentrations (Deegan et al., 2012). Research Needs Related to Vitamin B12 Lamers listed some key knowledge gaps related to vitamin B12. Recog- nizing low vitamin B12 status is an independent risk factor for neural tube defect, she suggested vitamin B12 trials using different doses were needed to determine a dose–response relationship. Noting that the dietary intake data suggest many pregnant women meet or exceed existing intake recommen- dations, she emphasized the need to identify women at risk of inadequate PREPUBLICATION COPY—Uncorrected Proofs

ONE-CARBON METABOLISM MICRONUTRIENTS 31 intakes and questioned whether the current recommendations are too low. Finally, she thought that additional research is needed to explore the change in vitamin B12 biomarker concentrations over the course of pregnancy and its relationships to functional outcomes. THE GROWING SCIENCE ON THE BENEFITS OF CHOLINE FOR MOTHERS AND INFANTS Marie Caudill, professor in the Division of Nutritional Sciences at C ­ ornell University, described the role of choline in fetal development. Caudill also provided an overview of the changes to choline metabo- lism during pregnancy, reviewed evidence on the relationship between choline intake during pregnancy and a range of outcomes, presented on choline intake levels among pregnant women in the United States, and discussed postnatal demands for choline. Role of Choline in Fetal Development Large amounts of choline are needed for fetal growth. ­Phosphatidylcholine, a derivative of choline, is important for cell membranes and cell division, and it is also needed for the synthesis of very low-density lipoproteins necessary for lipid transport from the maternal liver. Other choline derivatives play key roles in the development of the central nervous system. For instance, the developing hippocampus requires acetylcholine and the developing myelin sheath uses the choline derivative sphingomyelin. Choline is also need for cellular methylation reactions. There are a wide range of these types of reac- tions, including DNA methylation (an epigenetic modification) using the choline derivative betaine. Epigenetic modification of the fetal and placental genomes “can influence gene expression, protein synthesis, cellular func- tion, and ultimately have lasting effects on the health of the offspring,” said Caudill. Choline Metabolism and Needs During Pregnancy Phosphatidylcholine and free choline are the two main forms of dietary choline. In presenting Figure 3-1, Caudill described the different pathways for these compounds. Both forms of dietary choline can enter circulation and be provided to the fetus. Additionally, free choline in the maternal liver will be converted to phosphatidylcholine by one of two pathways: • Most free choline will go through the cytidine diphosphate–choline pathway (“CDP–choline pathway”). The resulting phosphatidyl- choline is enriched with a shorter-chain saturated fatty acid. PREPUBLICATION COPY—Uncorrected Proofs

32 NUTRITION DURING PREGNANCY AND LACTATION FIGURE 3-1  Maternal metabolism of choline and delivery to the fetus. NOTE: 16:0 = palmitic acid; CDP = cytidine diphosphate; CH3 = methyl group; CM = chylomicron; DHA = docosahexaenoic acid; MET = methionine; PC = phosphatidylcholine; PE = phosphatidylethanolamine; PEMT = phosphatidyletha- nolamine N-methyltransferase; SAM = S-adenosylmethionine; VLDL = very low- density lipoprotein; SOURCES: Presented by Marie Caudill. Reprinted from Korsmo et al., 2019, used under CC BY 4.0. • Some of the free choline will be routed through the phosphatidyl- ethanolamine N-methyltransferase pathway (“PEMT pathway”), where the choline-derived methyl groups are used to methylate phosphatidylethanolamine. The resulting phosphatidylcholine will be enriched with long-chain polyunsaturated fatty acids, like d ­ ocosahexaenoic acid (DHA). Tracer studies conducted in pregnant women show that phosphatidylcholine molecules produced by the PEMT pathway progressively increase from maternal circulation to the placenta to cord blood. “What this suggests is that there is a unique requirement for PEMT-phosphatidylcholine by the develop- ing fetus, and it is mostly likely related to its enrichment in DHA and other long-chain unsaturated fatty acids,” offered Caudill. Circulating choline-derived methyl donors are depleted during preg- nancy. Although folate can serve as a methyl donor, high folate intakes during pregnancy cannot compensate for the decreases in choline-derived methyl donors, stated Caudill. Tracer isotope studies have revealed two reasons for this depletion. First, pregnant women spare free choline for PREPUBLICATION COPY—Uncorrected Proofs

ONE-CARBON METABOLISM MICRONUTRIENTS 33 the CPD-choline pathway, rather than converting it to betaine. Second, pregnant women use more of the betaine and dimethylglycine (both c ­ holine-derived methyl donors) that are produced for cellular methylation and other one-carbon reactions. Conversely, concentrations of circulat- ing ­ holine and phosphatidylcholine increase during pregnancy. Pregnant c women upregulate both the CDP-choline and PEMT pathways to generate more phosphatidylcholine than nonpregnant women and convert more of the endogenously made phosphatidylcholine back to choline for transfer to the fetus. Infants are born with choline concentrations three to five times that of their mothers, noted Caudill. Evidence from studies of nonpregnant women of reproductive age indicates that choline and DHA have a synergistic relationship. As choline intakes increases, the PEMT-choline pathway is upregulated and hepatic DHA export increases (West et al., 2013). Caudill mentioned that deter- mining if this upregulation can increase delivery of DHA to the fetus is a current area of investigation. Effects of Higher Choline Intakes During Pregnancy Relationships between high maternal choline intakes and various meta- bolic responses and epigenetic measures have been investigated, observed Caudill. Higher choline intakes during pregnancy have been found to increase circulating betaine and dimethylglycine concentrations (Yan et al., 2012, 2013) and enhance placental DNA methylation (Jiang et al., 2012). Some of the metabolic disturbances stemming from variants in choline- and folate-metabolizing genes can also be overcome by higher choline intakes during pregnancy (Ganz et al., 2016, 2017). Pregnancy and infant outcomes have also been assessed in relation to high choline intakes. One study reported that women who consumed more than 498 mg/day of choline had a 50 percent reduction in neural ­ tube defects as compared to women consuming less than 290 mg/day of choline, independent of total folate intake (Shaw et al., 2004). In another study, plasma cortisol concentrations were 33 percent lower among infants whose mother consumed 930 mg/day of choline, as com- pared to infants whose mother consumed 480 mg/day of choline (Jiang et al., 2012). Caudill explained that the reduction in infant stress response ­ may be mediated through choline exerting epigenetic modifications; reductions in stress reactivity, in turn, may have long-term implications, reducing risk for certain chronic disease (e.g., depression, diabetes, hyper- tension, obesity) and improving learning outcomes (e.g., attention, learn- ing, memory). High choline intakes during pregnancy may also reduce the expression of the preeclampsia risk factor called soluble fms-like tyrosine kinase 1 (sFLT-1) (Jiang et al., 2013). PREPUBLICATION COPY—Uncorrected Proofs

34 NUTRITION DURING PREGNANCY AND LACTATION Investigators have also explored the relationship between maternal c­ oline intake and offspring’s cognitive function. In rodent studies, off- h spring whose mothers were supplemented in the prenatal period had sig- nificantly fewer errors on a 12-arm radial maze over the course of their life span and did not experience age-related increases in errors over time (Meck et al., 2003). High maternal choline intake in rodent models have also been shown to be protective against a range of neural insults in the offspring (e.g., Alzheimer’s disease, autism, Down syndrome, early-life iron deficiency, fetal alcohol syndrome) (Korsmo et al., 2019). Caudill characterized the evidence in humans as mixed, but noted that there is a growing body of evidence to suggest that higher maternal choline intake during pregnancy may improve certain aspects of children’s cognitive function. For instance, infants of mothers who consumed 930 mg choline/ ­ day throughout the third trimester appear to have faster information pro- cessing speeds at 1 year of age, as compared to infants whose mothers consumed 480 mg choline/day (Caudill et al., 2018). Preliminary evidence suggests differences between these two groups persist; at 7 years of age, children whose mothers were supplemented had superior attention, visual memory, and problem solving (Bahnfleth et al., 2019). Acknowledging the small sample size in this study, Caudill added that these findings are con- sistent with what has been reported in animal studies, a large prospective cohort study, and other randomized controlled trials. Choline Intake Levels Only 8 percent of pregnant women have intakes that meet the choline Adequate Intake of 450 mg/day. Rather, average choline intake is approxi- mately 322 mg/day, and it is lower among those consuming a vegetarian diet, as predominant sources of choline are animal sources. There are common genetic variants that can interfere with either folate or choline metabolism, which can further increase a woman’s gap between intake and needs, reported Caudill. Most of the leading prenatal vitamins do not contain choline, or if they do, it is in small amounts (25–50 mg). Caudill stated that compa- nies are increasing the amount choline in prenatal vitamins, a change that is supported by the American Medical Association. The American Academy of Pediatrics has recently called upon health care providers to ensure adequate choline is consumed during the first 1,000 days to support neurodevelopment.2 2  The first 1,000 days refers to the period from conception through a child’s second birthday. PREPUBLICATION COPY—Uncorrected Proofs

ONE-CARBON METABOLISM MICRONUTRIENTS 35 Postnatal Demands for Choline Infants have high demands for choline in the postnatal period, noted Caudill. Circulating choline concentrations are elevated in the first year of life. There is evidence to suggest concentrations above 14 μmol/L facilitate the transfer of choline across the blood–brain barrier. Lactating women have higher circulating choline concentrations than women who are not breastfeeding, which is thought to facilitate transfer of choline to breast milk (Ilcol et al., 2005). Building on this, Caudill showed that breast milk choline concentrations are approximately 15 times higher than circulating concentrations in the maternal blood (Ilcol et al., 2005). High maternal choline intake can increase the choline content of breast milk (Davenport et al., 2015). DISCUSSION After Caudill’s presentation, she and Lamers responded to questions from the audience. Topics explored included clinical considerations related to choline, recommendations for choline intake and supplementation, dose and formulation of folic acid supplementation, and considerations of folic acid in the food supply. Clinical Considerations Related to Choline Hatfield opened the discussion by admitting that choline was not a nutrient she assesses in her obstetric patients and wondered if choline should be included in routine prenatal labs. Agreeing that choline is an underappreciated essential nutrient, Caudill explained that there is no good biomarker for choline status. She suggested that knowing whether a woman consumes foods from animal sources could serve as a proxy. Following up on this comment, Emily Oken of the Harvard Medical School wanted to know which foods in particular contain choline. Identifying egg yolks as a good source, Caudill noted that animal flesh foods provide approxi- mately 100 mg/serving whereas cruciferous vegetables and legumes provide approximately 30–40 mg/serving. Oken also asked if conditions that affect the liver, such as fatty liver disorder, affect choline metabolism. Caudill indicated that it is possible, but that no studies have been conducted that show a higher need in this clinical population. Recommendations for Choline Intake and Supplementation Jessi Silverman of the Center for Science in the Public Interest wondered if the choline AI was appropriate. Caudill suggested that if optimization PREPUBLICATION COPY—Uncorrected Proofs

36 NUTRITION DURING PREGNANCY AND LACTATION of specific endpoints guides the selection of the AI, then there is evidence that 930 mg/day of choline is better than 480 mg/day, suggesting the cur- rent AI is too low. With the majority of pregnant women having choline intakes below the AI, raising the intake recommendation would elevate the importance of supplementation, Caudill offered. Given that prenatal formulations are including DHA, Johanna Dwyer of the National Institutes of Health’s Office of Dietary Supplements asked what dose of choline should be used in prenatal supplements. Noting that recommended intakes of choline is in milligrams per day, whereas other nutrients are in micrograms per day, Caudill explained that space ultimately limits the amount of choline that can be included in a pre­ atal formulation. n She mentioned that some companies are now looking to package choline with DHA in a single capsule. Caudill suggested that the dose of ­ holine for c a once-per-day capsule would likely need to be around 350–500 mg. She went on to describe concerns about excessive choline intakes. Set at 3,500 mg/day, the choline UL is based on evidence that unabsorbed choline can be metabolized by colonic bacteria, producing a fishy body odor. She further noted that concerns have been raised regarding high choline intakes promoting hypotension and worsening cardiovascular outcomes. With respect to the elevated choline needs of infants, Carolyn ­ ightower H of the Vitamix Foundation asked how infant formula choline content com- pares to breast milk concentrations. Caudill explained that the choline content depends on whether the infant formula is cow milk based (resulting in choline content similar to breast milk) or soy based (resulting in choline concentrations less than breast milk). She noted, however, that the form of choline in infant formulas is different from that found in breast milk, and there is evidence to suggest that it is less bioavailable. Dose and Formulation of Folic Acid Supplementation With a sizeable portion of pregnant women exceeding the periconcep- tional recommendations and the UL for folic acid, Hatfield questioned why prenatal supplements contain such a high dose of folic acid. Lamers thought that the 800 µg dose found in U.S. and Canadian prenatal supplements is historical. Hatfield also wondered what dose of folic acid supplementation should be given to a woman who has had neural tube defects in prior preg- nancies. Lamers explained that a trial from the United Kingdom showed that a periconceptional 4 mg/day dose of folic acid prevented recurrent neural tube defects. The selected dose of folic acid used in latter trial was a matter of convenience, as it was available in the hospital conducting the study. Given the significant findings, it is now not ethical to test a lower dose, so there is a lack of dose–response data for this outcome. She sug- gested that observational studies may eventually point to a lower dose. PREPUBLICATION COPY—Uncorrected Proofs

ONE-CARBON METABOLISM MICRONUTRIENTS 37 Recognizing that some prenatal supplement companies are using m ­ ethylfolate in their products rather than folic acid, Caudill wondered if there are any concerns with respect to the prevention of neural tube defects. Acknowledging that the two forms are biologically different, Lamers noted that 5-methyltetrahydrofolate increases red blood cell folate concentrations more than an equimolar amount of folic acid. She continued, by stating that neural tube defects have been shown to be prevented by 400 μg/day folic acid, so it is unethical to recommend a different folate form, as the mecha- nisms underlying its protective effects are not well understood. Considerations of Folic Acid in the Food Supply A member of the webcast viewing audience questioned why the United States and Canada had differences in reductions in neural tube defects with the introduction of folic acid fortification of foods. Lamers admit- ted that the cause of the difference is not known but thought it may be caused in part by different data collection approaches. Another member of the webcast audience wanted to know if folic acid intake is affected if a woman limits or avoids gluten. Lamers stated that foods that contain gluten (e.g., wheat flour and wheat-based products) are often the ones that are fortified with folic acid, so it could affect intake. She noted, however, that fortified foods only account for approximately 150 μg/day folic acid intake and underscored the need for periconceptional folic acid supplemen- tation in all women. PREPUBLICATION COPY—Uncorrected Proofs

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Nutrition During Pregnancy and Lactation: Exploring New Evidence: Proceedings of a Workshop Get This Book
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The National Academies of Sciences, Engineering, and Medicine last reviewed the state of the science on nutrition during pregnancy and lactation 30 years ago. The resulting consensus study reports from the Institute of Medicine—Nutrition During Pregnancy (IOM, 1990) and Nutrition During Lactation (IOM, 1991)—summarized the scientific evidence and provided nutrient recommendations. In the decades since the release of these two reports, the body of evidence on the relationships between nutrition during pregnancy and lactation and maternal and infant health and chronic disease has continued to grow and evolve. At the same time, the demographics of the population have shifted, giving rise to new considerations. To explore the evidence that has emerged, the National Academies conducted a 2-day workshop in January 2020. This publication summarizes the presentations and discussions from the workshop.

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