Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline (1998) / Chapter Skim
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8 Folate
8 Folate
Pages 196-305
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From page 196... ...
for folate is erythrocyte folate in conjunction with plasma homocysteine and folate concentrations. The RDA for both men and women is 400 ~g/day of dietary folate equivalents (DFEs)
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The Tolerable Upper Intake Level (UL) for adults is set at 1,000 ~g/day of folate from fortified food or as a supplement, exclusive of food folate.
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cletermineci average liver folate concentrations to be approximately 8 ~g/g (range 3.6 to 14.8 ~g/g) after autopsy; the liver folate content would be approximately 11 mg and total body folate 22 ma.
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Fecal folate losses occur, but it is difficult to distinguish actual losses from losses of folate synthesized by the intestinal microflora (Krum~ieck et al., 1978~. Clinical Effects of Inadequate Intake Inacloquate folate intake first leacis to a decrease in serum folate concentration, then to a decrease in erythrocyte folate concentration, a rise in homocysteine concentration, and megaloblastic changes in the bone marrow and other tissues with rapidly clivicling cells.
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Atrophic glossitis may also occur (Savage et al., 1994~. SELECTION OF INDICATORS FOR ESTIMATING THE REQUIREMENT FOR FOLATE The primary indicator selected to determine folate acloquacy is erythrocyte folate, which reflects tissue folate stores, as clescribeci in detail below.
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Erythrocyte folate concentration was shown to be related to tissue stores by its correlation, although weak, with liver folate concentration cletermineci by biopsy in the same incliviclual in a study of 45 subjects (Wu et al., 1975~. Erythrocyte folate concentration floes not reflect recent or transient changes in clietary folate intake.
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From page 202... ...
; at this level of intake plasma homocysteine concentrations were inversely associated with erythrocyte and serum folate concentrations (O'Keefe et al., 1995~. · In a cross-sectional analysis involving elderly inclivicluals, plasma homocysteine exhibited a strong inverse association with plasma folate after age, gentler, and intakes of other vitamins were controlleci for (Selhub et al., 1993~; homocysteine values appeared to plateau at folate intakes greater than approximately 350 to 400 fig/ clay.
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From page 203... ...
Although plasma homocysteine is a sensitive indicator of folate status, it is not a highly specific one: it can be influenced by vitamin BE status (Stabler et al., 1996) , vitamin B6 status (Ubbink et al., 1995a)
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From page 204... ...
In a controlled metabolic study, repeated measures over time in the same incliviclual do reflect changes in status. Serum folate concentration may be a worthwhile diagnostic test if used and interpreted correctly in conjunction with other folate status inclices (Linclenbaum et al., 1988~.
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Risk of Neura;t Tube Defects and of Chronic Degenerative Diseases The role of folate in the prevention of neural tube defects (NTDs) was very carefully consiclereci, but not in the context of setting an EAR.
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Measurement and Reporting of Food Fo;tate It is recognized that food folate composition ciata contained in currently used databases provide inaccurate estimations of folate intake of the U.S. population.
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. Many studies of population groups have used food composition databases and measures of food intake to estimate folate intake.
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Daly and coworkers (1997) reported incremental increases in erythrocyte folate in response to gracleci closes of folic acid, which provides eviclence for the high bioavailability of supplemental folate.
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. In the South African studies of folate-cleficient pregnant women, the response criterion used to estimate bioavailability was either 2-hour changes in serum folate or changes in erythrocyte folate over time.
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times more available. Thus, if a mixture of folic acid plus food folate has been feci, clietary folate equivalents (DFEs)
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. Cigarette Smoking Although blood folate concentrations have been reported to be
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Few studies, however, have controlled for potential differences in clietary folate intake between groups of anticonvulsant users and nonusers (Collins et al., 1988~. Thus, definitive conclusions cannot be drawn relative to adverse effects of these drugs on folate status.
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From page 213... ...
As expecteci, folate metabolism is uncler genetic control, and genetic heterogeneity exists. To estimate the relative contribution of genetic and environmental factors in determining folate status, erythrocyte folate was measured in monozygotic and clizygotic twins (Mitchell et al., 1997~; however, clietary intake was not assessed.
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From page 214... ...
Inclivicluals homozygous for the MTHFR T677 allele have significantly elevated plasma homocysteine (Frosst et al., 1995) and a tendency to have low plasma and erythrocyte folate concentrations (Ma et al., 1996; Molloy et al., 1997; Schmitz et al., 1996)
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From page 215... ...
Aciclitionally there are no reports of fullterm infants who are exclusively and freely feci human milk manifesting any signs of folate deficiency. The folate concentration of human milk remains relatively constant regardless of maternal clietary folate intake unless there is a severe maternal deficiency (Metz, 1970~.
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From page 216... ...
Smith and coworkers (1985) reported that throughout the first 6 months, serum folate concentrations were significantly higher in infants feci formula than in those feci human milk; erythrocyte folate concentrations of approximately 2,200 nmol/L (1,000 ng/mL)
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The resulting EARs are 120 and 160 ~g/day of DFEs for children ages 1 through 3 and 4 through 8 years, respectively. Foliate EAR and RDA Summary, Ages ~ through ~ Years EAR for Children 1-3 years 4-8 years 120 1lg/day of dietary folate equivalents 160 1lg/day of dietary folate equivalents The RDA for folate is set by assuming a coefficient of variation (CV)
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d Analyzed using older methods that may have underestimated the folate content. e Values were estimated from f~gures.
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1 of 4 had marginal erythrocyte folate. 2 of 5 had marginal erythrocyte and serum folate.
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A for Girls 9-13 years 300 ~g/day of dietary folate equivalents 14-18 years 400 ~g/day of dietary folate equivalents Adu;tts Ages I 9 through 50 Years Evidence Considered in Estimating the Average Requirement No single indicator was jucigeci a sufficient basis for deriving an EAR for adults. That is, it was not deemed appropriate to base the EAR on an examination limited to studies that provided data only
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From page 221... ...
, and repletion of severe clinical folate deficiency (Hansen and Weinfelci 1962; Herbert, 1962a, 1968; Marshall and Jancil, 1960; Zalusky and Herbert, 1961 ~ . Analyses of relationships of dietary folate intake and biochemical indices of folate status from the Third National Health and Nutrition Examination Survey are in progress and were thus unavailable for use in this report.
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Milne et al., Maintenance 40 men, NAG 2-8 mo 200 1983 19-54 y Sauberlich Depletion- 3 women, 400d 28 d depletion 0 et al., 1987 repletion 21-40 y 21 d repletion 100 2 women 400d 28 d depletion 0 21 d repletion 200 Jacob et al., Depletion- 10 men, 440e 30 d depletion 25 1994 repletion 33-46 y 15 d repletion 25 O'Keefe et al., Maintenance 5 women, NA 70 d 30 1995 21-27 y 6 women, NA 70 d 30 21-27 y a The EAR is the intake that meets the estimated nutrient needs of 50% of the individuals in a group. b To compute dietary folate equivalents, use the formula fig food folate + (1.7 x fig folic acid)
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. 30 270 489 Erythrocyte folate and plasma homocysteine were maintained in all.
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This level of intake maintained normal plasma homocysteine, erythrocyte folate, and serum folate values with no significant increase or decrease throughout the 70-clay maintenance study. Therefore, 489 ~g/day of DFEs could be considered to be above the average requirement.
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, and 21 days tSauberlich et al., 19871~; and (~) it provided folate largely in the form of folic acid, thus minimizing the possibility that folate intake was unclerestimateci.
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Zalusky and Depletion- Folate-free 60 1 male None Herbert, 1961 repletion synthetic diet Herbert, 1962a Depletion Folate-free diet 35 1 male Herbert, 1962b Depletion- Defined folate- NAC 1 female repletion deficient diet 1 female 1 female Krumdieck Kinetic Not reported 36 1 female etal.,l978 5 5 5 5 None Von der Porten Kinetic Self-selected diets 22-31 6 males 200e et al., 1992 Stites et al., 1997 Kinetic Self-selected, 20-30 4 males 443f folate-adequate diets a IM = intramuscular. b DFEs = dietary folate equivalents.
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and a decrease in erythrocyte folate concentration to < 305 nmol/L ( 140 ng/mL)
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A for Women 19-30 years 31-50 years 400 1lg/day of dietary folate equivalents 400 ~g/day of dietary folate equivalents 400 ~g/day of dietary folate equivalents 400 1lg/day of dietary folate equivalents Adu;tts Ages 5 ~ Years and Older The aging process has not been associated with a reduction in the ability to utilize folate (Bailey et al., 1984~. Folate status as measured by serum folate or erythrocyte folate has not been shown to decline as a function of age (Rosenberg, 1992; Selhub et al., 1993~.
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show that the mean homocysteine concentration begins to stabilize when folate intakes are approximately 300 ~g/ciay. Figure 8-2 presents data showing the relationship of plasma homocysteine to plasma folate concentrations (Lewis et al., 1992)
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Other studies Garry et al., 1982, 304 Caucasian men and 3-d diet records, Values fir 1984 women, 2 60 y prospective For nor erythro~ Sahyoun et al., 1988; 686 free-living adults, 3-d food records Median i Sahyoun, 1992; 2 60 y for won Rosenberg, 1992 NOTE: In these studies, it is impossible to calculate dietary folate equivalents because intake of foods fortified with folic acid was not specified. Moreover, on the basis of data from Tamura et al.
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For nonusers, 75% had folate intakes < 250 1lg/d. Overall, < 3% had erythrocyte folate of < 305 nmol/L (140 ng/mL)
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FIGURE 8-2 Relationship of plasma homocysteine concentrations to plasma folate concentrations in 209 adult males. A indicates lower limit of normal plasma folate as used by the Second National Health and Nutrition Examination Survey (6.8 nmol/L)
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When folate intake is inacloquate, maternal serum and erythrocyte folate concentrations decrease and megaloblastic marrow changes may occur (Picciano, 1996~. If inacloquate intake continues, megaloblastic anemia may develop.
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, who found that taking 150 ~g/ciay of folate supplements (beginning at 28 weeks) in aciclition to cliet resulted in low serum folate concentrations (less than 7 nmol/L t3 ng/mL]
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Folate status was normal (serum folate greater than 7 nmol/L t3 ng/mL] and erythrocyte folate values greater than 305 nmol/L t140 ng/mL]
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has been shown to be sufficient to maintain normal folate status cluring pregnancy. When expressed as DFEs, the consistent fincling across the numerous population studies and the controlled metabolic study is that 600 ~g/ciay of DFEs is acloquate to maintain normal folate status.
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McPartlin and colleagues (1993) quantitatecT the urinary excretion of the major folate catabolites in six pregnant women and six nonpregnant control subjects.
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. Data from the controlled metabolic study support an RDA of 600 ~g/day of DFEs baseci on maintenance of normal erythrocyte folate concentrations and agree with the finclings from the series of population studies that 600 ~g/day of DFEs is adequate to maintain normal folate status in groups of pregnant women.
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, clietary folate intake was estimated to be 400 ~g/ciay. In the unsupplementeci lactating women, plasma homocysteine concentrations increased significantly but remained well within the normal range (6 to 7 ~mol/L)
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Folate from supplements or fortified foocis in aciclition to clietary folate is recommencleci for women capable of becoming pregnant. REDUCING RISK OF DEVELOPMENTAL DISORDERS AND CHRONIC DEGENERATIVE DISEASE Neural Tube Defects Neural tube defects (NTDs)
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FOLATE 241 operation clone for that purpose) ; 20 percent are using highly effective contraceptives, usually long-term in nature; ~ percent are pregnant or immediately postpartum at any particular point in time; and 11 percent have never haci sexual intercourse.
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Closure of the neural tube begins separately and consecutively in at least three sites: the cervical-hincibrain boundary, the forebrain-micibrain boundary, and the rostral extremity of the forebrain. Closure spreads to the intervening regions with completion of neural tube formation at neuropores in the forebrain (anterior neuropore)
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FOLATE 243 TABLE 8-6 Total Prevalence Rates of Neural Tube Defect in Selected Areas of North America, from Birth Defect Registry Data, 1985-1994 Area Prevalence Rate per 1,000 95% Confidence Interval Arkansas 1.03 0.85-1.24 Atlanta 0.99 0.78-1.23 California 0.94 0.87-1.01 Iowa 0.90 0.78-1.07 Hawaii 0.72 0.59-0.87 Quebec, Canada 1.41 0.95-2.01 SOURCES: Cragan et al.
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From page 244... ...
Data from demographic, family, and mouse model studies have prompted a search for cancliciate genes that predispose inclivicluals to an NTD. A defect in enzymes involved in homocysteine metabolism is suggesteci by altered folate, vitamin Bit, homocysteine, and methylmalonate values in mothers of infants with NTDs (Mills et al., 1995; Steegers-Theunissen et al., 1994~; the prevention of some human NTDs by folate administration; and the prevention of NTDs in some rodent models by methionine (Essien, 1992; Vanaerts et al., 1994~.
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The polymorphism was recently associated with low erythrocyte folate values (Molloy et al., 1997) , which suggests that these values by themselves could account for the increased NTD risk.
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The results have been inconsistent, some showing no association with NTD prevalence (Walci, 1994~. Others have clemonstrateci low or low normal levels of both vitamin BE and erythrocyte folate and suggested that both vitamins represent inclepenclent risk factors for NTD (Kirke et al., 1993~.
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(Tables 8-7 and 8-9) , folate supplement use and clietary folate intake cluring the periconceptional period were retrospectively assesseci by using a face-to-face interview and a semiquantitative food frequency questionnaire with mothers of children with NTDs and randomly selected controls.
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Atlanta NTDa case infants and normal control infants Pregnant women without a prior NTD-affected pregnancy Multivita contain folic ac before ~ throug! trimest' Bower and Stanley, Case/control in Spina bifida case infants and Dietary f 1989 (as reported Western Australia normal control infants multivit in CDC, 1992)
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An in risk t a prior 1 mo before increasing protective effect was y conception through observed from the lowest to the the 1st trimester highest quartile. Odds ratio = 0.25, p < 0.05 Formal Multivitamin plus folate 89 NTD cases in infants from No supplement containing supplemented women and 214 cases protective up to 0.8 mg of folic in infants from unsupplemented effect t a prior acid plus diet at least women 1 mo before conception through the 1st trimester 90 normal infants from supplemented women and 196 normal infants from unsupplemented women controls Odds ratio = 0.91, not statistically significant Formal Multivitamin plus folate 10 NTD pregnancies among 10,713 72% supplement containing women who took multivitamin reduction 0.1-1.0 mg of folic acid plus folate in risk t a prior plus diet at least 1 mo y before conception 39 NTD pregnancies among 11,944 through the 1st trimester women who took multivitamins without folate Relative risk = 0.28, p < 0.05 continued
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TABLE 8-8 Controlled Trials Relating Folate Supplementation and Risk of Neural Tube Defect in the Periconceptual Period Study Design Subjects Exposur. Randomized controlled trials—previous NTD pregnancy Laurence et al., 1981 Randomized Pregnant women with prior 4 mg of controlled trial NTDa-affected pregnancy; placebo in Wales supplemented mothers took 1 mo b.
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ntation erioci Exposure Results Comments -ior 4 mg of folic acid or 2 NTD pregnancies in 60 60% cy; placebo daily at least supplemented women reduction took 1 mo before conception in risk through the 1st 4 NTD pregnancies in 51 trimester placebo-treated women rs took Relative risk= 0.40, not statistically significant -ior 4 mg of folic acid or 6 NTD pregnancies in 593 72% y placebo daily at least supplemented women reduction 1 mo before conception in risk took through the 1st 21 NTD pregnancies in 602 trimester unsupplemented women rs took Relative risk = 0.28, p < 0.05 continued
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From page 252... ...
0.36 mg of folic acid with or missed without multivitamins daily Unsupplemented women took multivitamins daily excluding folic acid Nonrandomized controlled trials previous NTD pregnancy Smithells et al., 1983 Nonrandomized Pregnant women with prior 0.36 mg controlled NTD-affected pregnancy multivit multicenter trial from 1 in UK Supplemented mothers took concept 0.36 mg of folic acid plus 1st trim multivitamins daily Unsupplemented mothers took nothing Vergel et al., 1990 Nonrandomized Pregnant women with prior 5 mg of controlled trial NTD-affected pregnancy use fro, in Cuba concept Supplemented mothers took 1st trim 5 mg of folic acid daily Unsupplemented mothers took nothing Randomized controlled trial all women planning pregnancy Czeizel and Dudas, Randomized Women planning a pregnancy Supplem 1992 controlled trial at least in Hungary Supplemented women took concept 0.8 mg of folic acid plus the cat. multivitamins daily missed Unsupplemented women took a trace-element supplement a NTD = neural tube defect.
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From page 253... ...
FOLATE 253 Exposure Results Comments -ior Supplements taken for at 0 NTD in 172 infants/fetuses of Trial was y least 2 mo before supplemented women prematurely conception and until terminated wok the date of the third 1 NTD in 89 infants/fetuses of th or missed menstrual period unsupplemented women laity Indeterminate protective effect, ~ took not statistically significant luding -ior 0.36 mg of folic acid plus 3 NTD pregnancies in 454 86% y multivitamins or no use supplemented women reduction from 1 mo before in risk took conception through the 24 NTD pregnancies in 519 us 1st trimester unsupplemented women rs took Relative risk = 0.14, p < 0.05 -ior 5 mg of folic acid or no 0 NTD pregnancies in 81 Complete y use from 1 mo before supplemented women protective conception through the effect took 1st trimester 4 NTD pregnancies in 114 untreated women rs took Indeterminant protective effect, not statistically significant nancy Supplements taken for 0 NTD pregnancies in 2,104 Complete at least 1 mo before supplemented women protective wok conception and until effect s the date of the second 6 NTD pregnancies in 2,052 missed period unsupplemented women took a Relative risk = 0.0, p= 0.029 nt
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From page 254... ...
The data do not allow the computation of dietary folate equivalents in toto because intake of folic acid from fortified foods is not available. Both studies were conducted in the United States prior to mandatory folate fortification.
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From page 255... ...
Values that include folate supplements (indicated by a) are estimated in dietary folate equivalents (1 dietary folate equivalent = 1 fig food folate = 0.6 fig folate from fortified food or as a supplement taken with food = 0.5 fig supplemented folate when fasting)
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From page 256... ...
The erythrocyte folate concentration is a marker of long-term folate status. Studies looking for an association of erythrocyte folate with NTD risk baseci on estimating erythrocyte folate levels in blood samples taken early in pregnancy are preferred because maternal folate status is likely to change cluring pregnancy and postpartum.
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From page 257... ...
The percentage of women using folate supplements was ~ percent. A negative apparently nonlinear association was observed between NTD risk and erythrocyte folate concentration (Table 8-10~.
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Erythrocyte folate concentrations improved significantly only in the groups taking folate supplements or food fortified with folate; there was no increase in the group provicleci extra food folate or clietary acivice. Because food intake was not controlled, further studies are neecleci to evaluate more precisely the relative efficacy of different supplementation regimens in reducing NTD risk.
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From page 259... ...
and erythrocyte folate concentration (Daly et al., 1995~. Although it is recognized that there are still uncertainties about the relationships among folate intake, erythrocyte folate, and NTD risk and the extent to which there are differences in the absorption of folate from food compared with supplements, the evidence is still jucigeci sufficient to support a recommendation to recluce the risk of NTD.
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reported that plasma homocysteine values were a strong predictor of mortality in patients with angiographically confirmed coronary artery disease. The mechanism by which elevated homocysteine might increase the risk of developing vascular disease is unclear.
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From page 261... ...
As seen in Figure 8-5, the inverse association between mean clietary folate and mean homocysteine concentration is not linear but seems to reach a plateau at total folate intake levels greater than 300 ma/ clay. A review of seven studies indicates that homocysteine concentrations are also inversely correlated with plasma folate concentrations, and there seems to be a serum folate concentration around 9 nmol/L (4 ng/mL)
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_ I 86 4 2 o DIETARY REFERENCE INTAKES 1d 1ab 1c 2 2b2eC ·. 3a · 3c 3b ~ 1f 1e 2d 4 1 1 1 1 1 1 1 1 1 // 1 ' 0 200 400 600 800 5,000+ Total Folate Intake (,ug/day)
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However, there are conflicting data on the association among indicators of folate status or metabolism, homocysteine concentration, and risk of vascular disease. Whether increasing intake of folate could reduce the risk of vascular disease remains to be demonstrated.
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. Subjects with the HPV-16 infection had a fivefold greater risk of having dysplasia if they also had diminished erythrocyte folate values (660
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Colorectal Cancer Data supporting the modulation of carcinogenesis by folate status are the strongest for the colorectum. Patients with chronic ulcerative colitis are at increased risk for colonic cancer and also coexisting folate deficiency.
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~ but was still well within the normal range, which is in line with observations of erythrocyte folate concentrations and dysplasia in the uterine cervix (Butterworth et al., 1992a)
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~ was found to be 15 to 17 percent, a value substantially higher than the 2 percent found in control subjects (Abou-Saleh and Coppen, 1989~; erythrocyte folate was also measured and found to correlate highly with plasma folate concentrations.
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In these studies, there appears to be no uniform definition of folate deficiency (as inclexeci via the plasma or erythrocyte folate cletermination) ; moreover, folate assays (anci absolute folate values)
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Summary of Evidence Concerning the Risk of Developmental Disorders and Chronic Degenerative Disease Reducing the Risk of NTD Uncertainties still exist about the relationships among folate intake, erythrocyte folate, and NTD risk and about the extent to which the effect of food folate should be clistinguisheci from the effect of folate from supplements or fortified foocis, but the evidence is jucigeci sufficient to sunnort a specific recommendation to recluce the risk of NTD.
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From page 270... ...
are so commonly eaten that their contribution to total folate intake is relatively high. As of January 1, 1998, all enriched cereal grains (e.g., enriched breaci, pasta, flour, breakfast cereal, and rice)
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From page 271... ...
of folate a value set by the Food and Drug Administration. Values do not represent dietary folate equivalents; expressed as dietary folate equivalents, values for ready-to-eat cereals or other food fortified with folate would be higher.
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From page 272... ...
conclucteci from 1981 to 1984 estimated that this relatively advantaged group of people over age 60 who were not taking supplements haci meclian folate intakes of 254 ~g/ciay for men and 208 ~g/ciay for women. Intake from Supplements Results of a nationwide telephone survey conclucteci cluring January and February 1997 inclicateci that 43 percent of women of childbearing age reported taking some form of vitamin supplement containing folate.
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Largely because of supplement use, the meclian folate intake by pregnant women in NHANES III in 1988 to 1994 was nearly 1,000 ~g/day (Appendix H)
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Third, a metabolic interaction between folate and vitamin BE is well clocumenteci (Chanarin et al., 1989~. Although the association between folate treatment and neurological damage observed in human case reports floes not provide proof of causality, the hazard associated with excess supplemental folate cannot be ruled out.
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From page 275... ...
(1990) in which the subjects were vitamin B12 def~cient but did not have pernicious anemia.
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From page 276... ...
to prevent neural tube defects (Table 8-13~. No adverse effects have been clemonstrateci, but the studies were not specifically clesigneci to assess adverse effects.
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, who found high serum folate concentrations to be associated with favorable pregnancy outcomes including higher birth weight and Apgar scores of newborns, recluceci prevalence of fetal growth retardation, and lower incidence of maternal infection close to the time of delivery. Summary The weight of the limited but suggestive evidence that excessive folate intake may precipitate or exacerbate neuropathy in vitamin B~2-cleficient inclivicluals justifies the selection of this endpoint as the critical endpoint for the development of a UL for folate.
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From page 278... ...
Study was not designed to assess adverse effects. b Plasma folate was measured at different times in pregnancy, but compliance with prenatal vitamin use was not recorded.
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From page 279... ...
. · in most cases throughout the close range, folate supplementahon maintained the patients in hematological remission over a consiclerable time span; and · the background intake of folate from food was not specified, but all except for three cases (those reported by Allen and coworkers [ 1990]
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From page 280... ...
No ciata were found to suggest that other life stage groups have increased susceptibility to adverse effects of high supplemental folate intake. Therefore, the UL of 1,000 ~g/ciay is also set for adult pregnant and lactating women.
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From page 281... ...
Baseci on ciata from NHANES III and excluding pregnant women (for whom folate supplements are often prescribed) , the highest reported total folate intake from food and supplements
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From page 282... ...
It would be possible to exceed the UL of 1,000 ~g/ciay of folic acid through the ingestion of fortified foocis, supplements, or both, as inclicateci by the information on the folate content of foocis in Table 8-14. Risk Characterization The intake of folate is currently higher than inclicateci by NHANES III because enriched cereal grains in the U.S.
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From page 283... ...
, it is unlikely that intake of folate acicleci to foocis or as supplements would regularly exceed 1,000 fig for any of the life stage or gentler groups. RESEARCH RECOMMENDATIONS FOR FOLATE High-Pr~or~ty Recommendations Priority should be given to four topics of research related to folate: · Determination of the mechanisms and magnitude of relationships of folate intake with risk reduction for the occurrence of neural tube defects (NTDs)
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From page 284... ...
· Determination of the effect of folate fortification on folate intake and occurrence of NTD and vascular disease. · Determination of whether folate status affects the risk of birth defects other than NTDs and of chronic diseases other than vascular disease (e.g., cancer)
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From page 285... ...
1983. Neural tube defects in the Sikhs.
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From page 286... ...
1995. Maternal-fetal folate status and neural tube defects: A case control study.
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From page 287... ...
1997. Folate status response to controlled folate intake in pregnant human subjects.
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From page 288... ...
1996. Effect of increasing dietary folate on redcell folate: Implications for prevention of neural tube defects.
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From page 289... ...
1995. Folate levels and neural tube defects.
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1992. Maternal methionine supplementation promotes the remediation of axial defects in And mouse neural tube mutants.
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From page 291... ...
1997. Plasma homocysteine as a risk factor for vascular disease.
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From page 292... ...
1993. Neural tube defects and serum zinc.
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From page 293... ...
1991. Diagnosis and management of neural tube defects today.
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From page 294... ...
1993. Maternal plasma folate and vitamin B12 are independent risk factors for neural tube defects.
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From page 295... ...
1981. Double-blind randomized controlled trial of folate treatment before conception to prevent recurrence of neural tube defects.
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1996. Folate status of gastrointestinal epithelial cells is not predicted by serum and red cell folate values in replete subjects.
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From page 297... ...
1997. Genetic effects on variation in red-blood-cell folate in adults: Implications for the familial aggregation of neural tube defects.
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1994. Influence of smoking on folate intake and blood folate concentrations in a group of elderly Spanish men.
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From page 299... ...
1997. Are common mutations of cystathionine beta-synthase involved in the aetiology of neural tube defects?
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From page 300... ...
1998. Preconceptional folate intake and malformations of the cardiac outflow tract.
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1995c. Periconceptional vitamin use, dietary folate, and the occurrence of neural tube defects.
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Maternal hyperhomocysteinemia: A risk factor for neural tube defects? Metabolism 43:1475-1480.
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From page 303... ...
1990. Primary prevention of neural tube defects with folic acid supplementation: Cuban experience.
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1993. Periconceptional folic acid exposure and risk of occurrent neural tube defects.
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From page 305... ...
1995. A genetic defect in 5, 10 methylenetetrahydrofolate reductase in neural tube defects.
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