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Original Research Communications |
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Objective: We studied the effect of low-dose folic acid administration (250 or 500 µg/d) for 4 wk on plasma total homocysteine concentrations and folate status. We also investigated whether total homocysteine concentrations and blood folate concentrations returned to baseline after an 8-wk washout period.
Design: In this placebo-controlled study, 144 healthy women aged 18–40 y received 500 µg folic acid/d, 500 µg folic acid every second day (250 µg/d), or a placebo tablet with their habitual diet (mean dietary folate intake: 280 µg/d).
Results: Administration of 250 and 500 µg folic acid/d for 4 wk significantly increased folate concentrations in plasma (P < 0.001) and red blood cells (P < 0.01). Total homocysteine concentrations decreased significantly (P < 0.001) in women (n = 50) who took 250 µg folic acid/d [mean (±SEM) deviation from baseline: -11.4 ± 1.98%] and in women (n = 45) who took 500µg folic acid/d (-21.8 ± 1.49%). Eight weeks after the end of the intervention period (week 12), plasma total homocysteine concentrations in the folic acid–supplemented groups had not returned to baseline (week 0).
Conclusions: Doses of folic acid as low as 250 µg/d, on average, in addition to usual dietary intakes of folate significantly decreased plasma total homocysteine concentrations in healthy, young women. An 8-wk washout period was not sufficient for blood folate and plasma total homocysteine concentrations to return to baseline concentrations.
Key Words: Supplements • folic acid • folate • neural tube defects • homocysteine • cardiovascular disease • humans • women
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Folate is an important substrate in the remethylation of homocysteine to methionine. Steegers-Theunissen et al (6) showed that a subgroup of women who had previously experienced an NTD-affected pregnancy had higher plasma total homocysteine concentrations than healthy control women (6). A mildly elevated plasma total homocysteine concentration is suggested to be a marker for a defect in folate metabolism or for folate deficiency and is thus a risk factor for having a child with an NTD (7, 8).
High plasma total homocysteine concentrations are also considered a risk factor for cardiovascular disease. The prevalence of elevated plasma total homocysteine concentrations is higher in patients with coronary artery disease (9, 10), cerebrovascular (11, 12) and peripheral vascular diseases, and thrombosis (13, 14) than in healthy control subjects. Evidence is accumulating that folate is involved in the prevention of these diseases. Low folate concentrations in blood are associated with cardiovascular disease (9, 12, 15, 16) and folate intake is related to carotid artery stenosis (12).
Intakes of supplemental folic acid >650 µg/d are known to decrease plasma total homocysteine concentrations (17). Some studies have investigated the effect of low doses of supplemental folic acid on plasma total homocysteine concentrations (18–22). However, this is the first placebo-controlled, in-depth study of the effects of supplemental folic acid (as low as 500 µg every other day) on plasma total homocysteine concentrations in healthy subjects with normal plasma total homocysteine concentrations. If low doses of supplemental folic acid also decrease plasma total homocysteine concentrations, then intervention with foods rich in folate could also be an option to reduce plasma total homocysteine.
Therefore, the aim of the present study was to investigate whether an average daily intake of 250 or 500 µg supplemental folic acid decreases plasma total homocysteine concentrations in healthy women. In addition, we investigated whether plasma total homocysteine concentrations returned to baseline (week 0) within 8 wk after the intervention ended (week 12) and how these treatments affected plasma and red blood cell folate concentrations.
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SUBJECTS AND METHODS |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The study design was approved by the Medical Ethical Committee of the Wageningen Agricultural University. All subjects gave written, informed consent. The fieldwork of the study was performed at the Division of Human Nutrition and Epidemiology of the Wageningen Agricultural University.
Methods
After stratification by the use and type (brand) of oral contraceptives used, the women were divided at random (by alternation) into 3 intervention groups: 500 µg folic acid/d (500-µg group), 500 µg folic acid every other day (on average 250 µg/d; 250-µg group), or a placebo (placebo group) for 4 wk. To maintain the blind nature of the study, all subjects received 2 containers of tablets: one marked with a red sticker and one with a yellow sticker. The tablets were indistinguishable from each other in appearance and taste. Subjects received a diary and a calendar in which the days were alternately marked red and yellow. Subjects were asked to maintain their regular diet, but to refrain from consuming liver and marmite, a yeast extract. All subjects kept a diary in which they reported the intake of tablets, illnesses experienced, the days on which they menstruated, the days on which they did not take oral contraceptives, any extraordinary foods consumed, and excessive physical activity. To assess compliance, we counted any remaining tablets and checked the reported intake of tablets in the diaries. On the days blood was collected, subjects took their tablets after blood sampling. Tablets were always taken before breakfast. A 24-h recall was obtained from each subject once during the intervention period to check their intake of macronutrients and folate.
Venous blood samples were collected after subjects had fasted overnight, beginning at the start of the 4-wk intervention period (week 0); after 1, 2, and 4 wk of intervention (weeks 1, 2, and 4); and 4 and 8 wk after the intervention period ended (weeks 8 and 12). Total plasma homocysteine and plasma folate concentrations were determined in all blood samples. Red blood cell folate concentrations were assessed at baseline (week 0) and at the end of both the intervention (week 4) and washout periods (week 12). We determined plasma vitamin B-12 concentrations at the start of the intervention period.
Blood samples were drawn into EDTA-containing evacuated tubes (Venoject II; Terumo, Madrid). For the determination of plasma total homocysteine, plasma folate, and plasma vitamin B-12, samples were immediately placed on ice and centrifuged within 60 min at 3000 x g for 10 min at 4°C. Plasma was separated and stored at -35°C for folate and vitamin B-12 and at -80°C for plasma total homocysteine determination. For the determination of folate concentrations in red blood cells, hematocrit samples were analyzed and a 1:4 dilution of whole blood was stored in sodium ascorbate (10 g/L) at -35°C. The hemolysates were further diluted with IMx Folate RBC Lysis Reagent (Abbott Diagnostics, Maidenhead, United Kingdom) before measurement. Total homocysteine concentrations were measured by HPLC and fluorimetric detection (intra- and interassay CVs <8%) (23). All samples from each subject were analyzed in the same run. Folate concentrations in plasma and red blood cells and vitamin B-12 in plasma were determined with the IMx automated immunoassay system (Abbott Laboratories, North Chicago); the vitamin B-12 assay is based on microparticle technology (microparticle intrinsic factor assay) and the plasma and red blood cell folate assays are based on ion-capture technology. The intraassay CV of the folate assay varied between 3% and 6%, whereas the interassay CV varied between 6% and 10%, depending on the folate concentration. For vitamin B-12, both the intra- and interassay CVs were <5%.
Statistical analyses
The response to the various treatments was calculated for each subject as the change in plasma total homocysteine, plasma folate, or red blood cell folate between the start (week 0) and the end (week 4) of the intervention period. Estimation of group sizes was based on a 10% decrease in plasma total homocysteine concentrations after 4 wk of supplementation with 400 µg folic acid in young women in Germany (24). On the basis of these data, 50 women per group would be sufficient to detect a change in plasma total homocysteine of 1 µmol/L with a power of 90% and an 
of 0.05. Furthermore, changes in plasma total homocysteine and plasma and red blood cell folate were calculated per subject between the start of the intervention period and the end of the washout period (week 0 – week 12). The changes in folate and plasma total homocysteine concentrations were normally distributed. One-way analysis of variance was used to analyze differences in responses of and in baseline concentrations of plasma total homocysteine, folate, and vitamin B-12 among the 3 groups. When this analysis indicated a significant difference (P < 0.05), multiple comparisons were made by Student's t tests, using a significance level of P < 0.05/3 = 0.017 (to maintain an overall significance level of P < 0.05).
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RESULTS |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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). Although the subjects had been randomly assigned into the 3 groups, the baseline concentrations of plasma total homocysteine differed significantly among the groups. The mean dietary intakes of folate and macronutrients during the intervention period did not differ significantly among the 3 intervention groups. Subject compliance was determined to be good on the basis of tablet counts and food diaries. Twenty-three subjects forgot to take 1 tablet during the whole study period and only 5 subjects forgot to take 2 tablets.
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). The increases in plasma folate were significantly higher in the 500-µg group than in the 250-µg group (P < 0.001). During the 8 wk after the end of the intervention period, the so-called washout period, plasma folate concentrations decreased significantly in the 2 treatment groups compared with the placebo group. However, the plasma folate concentration between weeks 0 and 12 was still significantly higher in the 2 treatment groups than in the placebo group (P < 0.01). Red blood cell folate concentrations remained stable during the washout period.
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). Four weeks of supplementation with 500 µg folic acid every second day resulted in a decrease in the plasma total homocysteine concentrations of 11.4% compared with 0.8% in the placebo group (Figure 1). In the 500-µg group, plasma total homocysteine decreased 21.8%. No significant changes occurred in plasma total homocysteine concentrations between weeks 4 and 12 (during the washout period). At the end of the washout period, plasma total homocysteine concentrations in the 2 treatment groups were still significantly lower than those in the placebo group. The quintiles of subjects with the highest baseline plasma total homocysteine concentrations showed the most pronounced decrease in plasma total homocysteine (Figure 2).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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). Assuming that plasma total homocysteine is a valid functional index of folate status (18, 19), these results showed that the recommended period of folic acid use of 4 wk before conception is sufficient to improve folate status. Neural tube closure takes place during the third and fourth weeks of pregnancy. Our results suggest that even if women did not take folic acid before pregnancy, for example in the case of an unplanned pregnancy, it might still be worthwhile to start taking extra folic acid immediately after missing the first menstrual period because plasma total homocysteine and folate status improve after as little as 1 wk of supplementation.
The extent of the decrease in plasma total homocysteine was influenced by the initial plasma total homocysteine concentrations of the study subjects (Figure 2). Subjects in the fifth quintile of initial plasma total homocysteine concentrations showed a much greater decrease in plasma total homocysteine concentration after intervention with folic acid than did subjects with low initial plasma total homocysteine concentrations. This could not have been due to regression toward the mean because the placebo group did not show this phenomenon. These findings agree with the results of Ward et al (21). This also explains the discrepancy with the results of Ubbink et al (25), who showed a 42% decrease in plasma total homocysteine concentrations after 6 wk of supplementation with 650 µg folic acid/d. Their study population was men with hyperhomocysteinemia (
± SD: 28.8 ± 14.5 µmol/L), whereas our subjects had normal plasma total homocysteine concentrations (mean baseline concentration: 10.5 µmol/L; 25).
Despite random allocation of the treatments, the mean baseline homocysteine concentration in the 250-µg group was significantly lower than in the 500-µg group. These differences may have occurred by chance. They cannot be explained by differences in folate and vitamin B-12 concentrations because they were comparable in all 3 groups (Table 1).
During the 4 wk of intervention, plasma total homocysteine concentrations gradually decreased in women in the 250-µg group (Figure 1). In contrast, during the first 2 wk of intervention the decrease in the 500-µg group was more or less linear, whereas in the subsequent 2 wk the decrease was more gradual. An explanation may be that the plasma total homocysteine concentrations of many subjects in the 500-µg group had already plateaued between the second and fourth weeks of supplementation, whereas 4 wk of intervention with 250 µg/d was not sufficient to have this effect. Several studies suggest that a high dose of folic acid will have no additional plasma total homocysteine–lowering effect after a plateau has been reached. However, the lowest effective folate intake and the optimal duration of supplementation are not clear. The results depicted in Figure 2 suggest that, at least over a 4-wk intervention period, 500 µg/d has a more pronounced effect on plasma total homocysteine concentrations than does 250 µg/d.
Washout period
Eight weeks after the end of the supplementation period, plasma total homocysteine concentrations had not returned to baseline. Although plasma folate concentrations in the 250- and 500-µg groups decreased after supplementation had ceased, concentrations remained higher than those in the placebo group throughout the study period. This was not unexpected because the whole-body folate pool has a slow turnover of <1%/d (26). Therefore, plasma total homocysteine was expected to remain lower and blood folate concentrations were expected to remain higher than at the start of the study for 
3 mo.
Red blood cell folate concentrations did not change between the end of the intervention period and the end of the study (Table 2). This finding agrees with the suggestion that red blood cells incorporate folate at erythropoiesis (27, 28) and retain it during their whole life span (28). Data suggest that lowering plasma total homocysteine may have important implications for the prevention of cardiovascular diseases in the general population. Boushey et al (29) estimated that an increment in plasma total homocysteine of 5 µmol/L would result in an increase in the relative risk to 1.4. However, studies in which plasma total homocysteine–lowering therapy, eg, by folic acid supplementation, resulted in a reduction in the incidence of cardiovascular disease have not yet been reported.
Our results indicate that 4 wk of folic acid supplementation with an average daily dose of 250 or 500 µg decreases plasma total homocysteine by 11% and 22% (1.3 and 2.6 µmol/L), respectively. In this study we supplied the 250-µg group with 500 µg every other day. We think that this might have underestimated the effect in the 250-µg group because Kelly et al (30) showed that intake of >266 µg folic acid/d in addition to the normal diet leads to unmetabolized folic acid in the blood (30). This suggests that not all folic acid supplied is available for the remethylation of homocysteine to methionine. It is not clear whether this has negative effects or not, but possible negative effects of the use of supplemental folic acid should not be ignored (31–33). Therefore, the search for the lowest effective dose still remains important.
Although the question of whether a 250-µg/d dose long-term is as effective as a 500-µg dose still needs to be answered, this study showed that even a dose as low as 250 µg folic acid/d effectively lowered plasma total homocysteine concentrations and increased the folate status of young, healthy women. The fact that such low doses are effective suggests that intervention with natural food folate may also be feasible. Thus, the bioavailability of natural folates in foods should receive close attention (34). The results of this study indicate that food fortification with low doses of folic acid is a good option.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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2 Supported by the Dutch Prevention Fund (28-2559), The Hague. Pharmachemie BV, Haarlem, Netherlands, kindly supplied the folic acid and placebo tablets, and Abbott Diagnostics, Maidenhead, United Kingdom, provided the IMx diagnostic testing kits.
3 Address reprint requests to IA Brouwer, Department of Obstetrics and Gynaecology, University Hospital Nijmegen St Radboud, PO Box 9101, 6500 HB Nijmegen, Netherlands. E-mail: ingeborg.brouwer{at}staff.NutEpi.wau.nl.
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Significantly different from 250-µg/d group, P < 0.001.