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1 From the Northern Ireland Centre for Diet and Health, University of Ulster, Coleraine, United Kingdom, and the Department of Food Science and Human Nutrition, University of Florida, Gainesville.
2 Presented at the symposium Maternal Nutrition: New Developments and Implications, held in Paris, June 11–12, 1998. 3 Address reprint requests to H McNulty, Northern Ireland Centre for Diet and Health, University of Ulster, Coleraine, BT 52 1SA, United Kingdom. E-mail: H.McNulty{at}ulst.ac.uk.
ABSTRACT
Committees worldwide have set almost identical folate recommendations for the prevention of the first occurrence of neural tube defects (NTDs). We evaluate these recommendations by reviewing the results of intervention studies that examined the response of red blood cell folate to altered folate intake. Three options are suggested to achieve the extra 400 µg folic acid/d being recommended by the official committees: increased intake of folate-rich foods, dietary folic acid supplementation, and folic acid fortification of food. A significant increase in foods naturally rich in folates was shown to be a relatively ineffective means of increasing red blood cell folate status in women compared with equivalent intakes of folic acid–fortified food, presumably because the synthetic form of the vitamin is more stable and more bioavailable. Although folic acid supplements are highly effective in optimizing folate status, supplementation is not an effective strategy for the primary prevention of NTDs because of poor compliance. Thus, food fortification is seen by many as the only option likely to succeed. Mandatory folic acid fortification of grain products was introduced recently in the United States at a level projected to provide an additional mean intake of 100 µg folic acid/d, but some feel that this policy does not go far enough. A recent clinical trial predicted that the additional intake of folic acid in the United States will reduce NTDs by >20%, whereas 200 µg/d would be highly protective and is the dose also shown to be optimal in lowering plasma homocysteine, with possible benefits in preventing cardiovascular disease. Thus, an amount lower than the current target of an extra 400 µg/d may be sufficient to increase red blood cell folate to concentrations associated with the lowest risk of NTDs, but further investigation is warranted to establish the optimal amount.
Key Words: Neural tube defects • NTDs • women of reproductive age • food folates • folic acid • fortification • folic acid recommendations • folate recommendations
INTRODUCTION
In response to the established protective role of folic acid against both the recurrence (1) and the first occurrence (2) of neural tube defects (NTDs), national committees worldwide have set almost identical folate recommendations (3–5). To prevent the recurrence of NTDs, women are recommended to consume 4–5 mg folic acid/d in tablet form. This recommendation is clearly achievable only by supplementation of women identified as being at risk. To prevent the first occurrence of an NTD, women are recommended to consume an extra 400 µg/d in addition to usual folate intake from before conception until the 12th week of pregnancy. Three ways in which the recommendation for the prevention of a first occurrence of an NTD can be achieved have been suggested (3–5): 1) increased intake of foods naturally rich in folate, 2) dietary folic acid supplementation, and 3) food fortification. The implementation of this recommendation is proving difficult. The prevention of first occurrences of NTDs is, however, the more significant public health concern because these represent 95% of all NTD cases (3).
This report evaluates the recommendation for preventing the first occurrence of an NTD by reviewing studies that have examined the response of red blood cell folates (considered the best index of folate status) to intervention with additional dietary folate or supplemental folic acid in amounts up to the recommendation of 400 µg/d.
HOW EFFECTIVE ARE CURRENT FOLIC ACID RECOMMENDATIONS FOR PREVENTING THE FIRST OCCURRENCE OF AN NTD?
Implementing the current recommendations for preventing the first occurrence of an NTD is problematic for various reasons. The first difficulty is that in some cases the recommendation is aimed at women planning a pregnancy (3). However, an estimated 50% of pregnancies in the United Kingdom and the United States are unplanned (3, 6) and the malformations of NTDs occur during the fourth week postconception, usually before a pregnancy is confirmed. Thus, to be effective, any intervention aimed at preventing NTDs should be targeted to all women of childbearing age so that optimal periconceptional folate status can be achieved in the majority of those who may become pregnant.
A second problem in implementing the recommendation of an extra 400 µg/d from folate or folic acid supplements is that this amount represents a 3-fold increase in typical intakes of the vitamin, which are 200 µg/d in women (7–9). Thus, achieving the recommendation by food folates alone would require major dietary modifications unlikely to be reached by most women planning a pregnancy, not to mention those not planning to become pregnant.
An even greater problem lies in the fact that even when a significant increase in natural food folates is achieved experimentally, the results of one intervention study in healthy young women suggest that this is a relatively ineffective means of optimizing folate status compared with equivalent intakes of the vitamin as fortified food (10). This intervention study was designed to examine the relative effectiveness of the 3 suggested routes for meeting the recommendation for preventing a first occurrence of an NTD. Changes in red blood cell folate were examined in response to a 12-wk trial involving one of the following regimens in addition to usual dietary folate intake: supplements (400 µg folic acid/d), fortified food (400 µg folic acid/d), natural food folates (400 µg total folate/d), dietary advice (qualitative), or control diet. All 4 interventions increased intakes of folate or folic acid (Figure 1), but this change was reflected as increased folate status only in those women taking supplements or consuming fortified food. The consumption of extra folate in the form of foods naturally rich in the vitamin resulted in only a modest (nonsignificant) increase in red blood cell folate, even though these foods were provided to subjects throughout the 12-wk intervention (10). The obvious explanation for the differences in response is that the synthetic form of the vitamin (folic acid, a monoglutamate present in supplements and fortified foods) is more bioavailable than are natural food folates (11), which are polyglutamate derivatives and have to be converted to the monoglutamyl form for absorption in the jejunum. In addition, folic acid is more stable than are food polyglutamates (11), which are reduced derivatives of folate that are prone to cleavage (rendering the folate molecule inactive) during storage, preparation, and cooking (12).
FIGURE 1. . Mean changes in dietary folate or folic acid supplementation and effect on red blood cell folate concentrations in response to a 12-wk intervention. Female subjects were randomly assigned to receive one of the following regimens in addition to their usual dietary folate intake: folic acid supplements, 0.4 mg/d (group 1, n = 9); folic acid–fortified foods, 0.4 mg/d (group 2, n = 6); natural food folates, 0.4 mg/d (group 3, n = 10); dietary advice, qualitative (group 4, n = 7); or no intervention (group 5, n = 9). To convert red blood cell folate in nmol/L to ng/L, multiply by 0.44. *,**,***Significantly different from preintervention (paired t test): *P < 0.05, **P < 0.01, ***P < 0.001. Adapted from Cuskelly et al (10).
Supplements, although shown to be very effective in optimizing folate status in women (10), do not offer an effective strategy for the primary prevention of NTDs in the general population because of poor compliance, even in women who plan their pregnancies (13, 14). One study reported that only 30% of an interviewed sample of pregnant women in the United Kingdom had followed the official folic acid recommendations correctly (15). Thus, food fortification is seen by many as the only alternative likely to succeed in the general population.
FORTIFICATION WITH FOLIC ACID: NEW US LEGISLATION
In January 1998, the Food and Drug Administration of the US Department of Health and Human Services implemented new legislation requiring that enriched grain products be fortified with folic acid at a concentration of 1.4 µg/g product (16). This strategy, aimed at decreasing births affected by NTDs, is projected to result in a mean additional intake of 100 µg folic acid/d in the population [based on dietary modeling and on the assumption of equal bioavailability (17)]. However, fortification is a controversial issue, with safety concerns on one hand and concern that fortification should be at a level high enough to offer significant protection against NTDs on the other. Safety concerns have resulted in the decision in the United States to fortify foods with amounts of folic acid that almost certainly carry no risk (16) but that may turn out to be ineffective in preventing NTDs.
Outside the United States, the question of implementing mandatory fortification for the primary prevention of NTDs is still under debate. Currently in the United Kingdom, folic acid fortification of bread and breakfast cereal is permitted on a voluntary basis (3); thereby, the decision to consume foods fortified with the vitamin lies with the consumer. Many other European countries also permit the sale of foods fortified with folic acid and other vitamins, whereas others expressly forbid food fortification. In time, actual changes in the incidence of NTD pregnancies in the US population will enable the long-term benefits of folic acid fortification to be estimated, but it may be several years before such evidence becomes available.
WOULD AMOUNTS OF FOLIC ACID LOWER THAN CURRENT RECOMMENDATIONS BE EFFECTIVE IN PREVENTING NTDS?
The lowest amount of folic acid that will protect most women against an NTD-affected pregnancy is a critical question when mandatory fortification is being considered. This is because fortification, unlike supplementation, is untargeted; thus, ensuring that the required dose is delivered to the vast majority of women inevitably means that women with high intakes of the fortified staple will receive much higher doses than women with lower intakes. Although folic acid is considered to be nontoxic even at high doses (18), there remains some concern that its widespread, chronic use in fortification might mask pernicious anemia and therefore place the elderly at some risk by delaying the diagnosis and treatment of vitamin B-12 deficiency (19). Although this view is strongly questioned by some (20, 21), one thing is clear: the lower the effective dose, the lower the risk (however small) of exposure to high doses in some people.
One clinical trial aimed to establish the minimum effective folic acid dose needed to provide protection against NTDs (22). In this trial, 121 women were randomly assigned to receive 100, 200, or 400 µg folic acid/d or placebo for 6 mo. Analysis of red blood cell folate responses in those who completed the study (n = 95) showed significant increases in all folic acid–supplemented groups. On the basis of the established inverse relation between risk of NTDs and maternal red blood cell folate concentrations (23), it was possible to use the red blood cell folate responses to predict the effects of folic acid intervention in the range of 100–400 µg/d on NTD risk. The investigators predicted that a dose of 100 µg/d would reduce NTDs by >20%, whereas 200 µg/d would reduce the risk by 42%, compared with a predicted 47% reduction in risk for the 400-µg/d dose (22). Thus, little further benefit was provided by the official recommendation of 400 µg/d compared with a dose of half this amount.
Because the supplements used in this study (22) were given in addition to usual dietary intake (which was not measured in the study), the results are directly applicable to fortification and provide important information of relevance to the ongoing debate about food fortification. First, these results show that amounts of folic acid lower than current official recommendations are likely to be very effective in preventing NTDs. A lower target dose for fortification would mean a lower exposure to the vitamin in the general population. Second, these results indicate that the new fortification policy in the United States (projected to result in an additional intake of 100 µg folic acid/d) will produce an important decrease in NTD, but that this measure alone will clearly not prevent all preventable cases. Therefore, in the United States as elsewhere, women of reproductive years should continue to be targeted to increase their folate intake.
ARE THERE ANY OTHER POTENTIAL HEALTH BENEFITS OF FOLIC ACID FORTIFICATION?
Folic acid fortification clearly would be beneficial in alleviating the folate deficiency and suboptimal folate status that arise as a result of decreased folate availability, increased requirements, or both. Whereas certain drugs (eg, phenytoin, aminopterin, pyrimethamine, sulfasalazine, and oral contraceptives) (24), alcohol (25), and smoking (26) are all known to compromise folate status, low dietary intake appears to be a contributory factor in many cases (25) and is considered to be the most common cause of suboptimal folate status (26). Likewise, the ability of a mother to sustain the increased folate demands of pregnancy will be considerably reduced if her habitual diet is low in folate. Red blood cell (and serum) folate concentrations decline throughout pregnancy, but not when the mother is supplemented with folic acid or when her folic acid intake is sufficient to meet the increased requirements of pregnancy (27). Folate-responsive megaloblastic anemia has been reported to occur in up to 24% of unsupplemented pregnancies in certain parts of Asia, Africa, Central American, and South America and in 2.5–5.0% of those in the developed world (28). Considerable evidence indicates that suboptimal folate status during pregnancy is not only associated with poor health outcome in the mother, but also has implications for the newborn. Goldenberg et al (29) reported a positive association between maternal folate status, birth weight, and reduced risk of fetal growth retardation in the United States. Thus, although folate status up to 28 d postconception is critical for the normal closure of the neural tube and the prevention of NTDs, folate status throughout pregnancy has other important implications for maternal, fetal, and neonatal health.
Although folate status is important throughout pregnancy and in other situations of increased requirement, it is the role of folic acid as a homocysteine-lowering agent that is of greatest current interest. Elevated plasma homocysteine concentrations have been identified as an independent risk factor for vascular disease (30). Folate is essential for homocysteine metabolism and suboptimal folate status is considered to be the most common reason for elevated plasma homocysteine concentrations. Thus, administration of folic acid is well documented to lower plasma homocysteine concentrations (31, 32). A recent meta-analysis of 12 randomized controlled trials of supplementation with folic acid, which included 1114 individuals, showed that folic acid in the range 0.5–5 mg/d lowers homocysteine by 25% (33).
One intervention study examined red blood cell folate and homocysteine lowering in response to low-dose folic acid in the range of 100–400 µg/d over 26 wk (34). Healthy male volunteers (n = 30) were given folic acid in daily doses that increased from 100 µg (6 wk) to 200 µg (6 wk) to 400 µg (14 wk). Plasma homocysteine concentrations decreased significantly in response to 100 µg folic acid/d and decreased further when the dose was increased to 200 µg/d. However, supplementation with 400 µg/d did not cause any additional decrease in homocysteine concentrations, suggesting that 200 µg folic acid/d may be an optimal homocysteine-lowering dose (34). Of greater interest, when the results were expressed as tertiles of baseline plasma homocysteine concentration, the significant homocysteine-lowering effects were achieved in only the top (10.90 ± 0.83 µmol/L) and middle (9.11 ± 0.49 µmol/L) tertiles. Corresponding red blood cell folate concentrations at baseline in these tertiles were 894 ± 188 and 1003 ± 300 nmol/L (394 ± 83 and 442 ± 132 µg/L), respectively. In the lowest tertile, in which the mean baseline homocysteine concentration was 7.07 ± 0.84 µmol/L and baseline red blood cell folate was 1280 ± 563 (564 ± 248 µg/L), no significant response to folic acid supplementation (at any dose) was observed. Thus, in the group as a whole, the lowering of plasma homocysteine clearly occurred most in those with the highest baseline homocysteine (and lowest red blood cell folate) values, to a lesser extent in those with intermediate values for both indexes, and not at all in those with the lowest homocysteine (and highest red blood cell folate) values at baseline (34). In addition, in subjects in the lowest tertile of baseline homocysteine concentrations, red blood cell folate concentrations showed no significant increase in response to 6 mo of folic acid supplementation (up to 400 µg/d), suggesting that baseline folate status was optimal to begin with in this group. In contrast, concentrations increased significantly in each of the other 2 tertiles, indicative of suboptimal folate status at baseline. It is worth noting that none of these subjects had a red blood cell folate value below the reference range used to define low status or deficiency.
The results of this study therefore suggest that approximately two-thirds of apparently healthy individuals have plasma homocysteine concentrations that can be lowered in response to folic acid supplementation and that this lowering is reflected in an increase in red blood cell folate concentrations (34). The finding that optimal homocysteine lowering can be achieved with a dose as low as 200 µg folic acid/d has important implications for fortification programs and for large-scale, randomized trials conducted to determine whether lowering blood homocysteine concentrations reduces the risk of vascular disease. Unnecessarily high doses of folic acid should be used in neither.
CONCLUSIONS
For practical as well as physiologic and chemical reasons, mandatory fortification of staple foods with folic acid offers the best strategy for the primary prevention of NTDs. The introduction of such a strategy (as in the United States) is likely to have other positive benefits as well, including a potential role in preventing vascular disease. Recent studies of red blood cell folate responses to intervention suggest that amounts of folic acid lower than the current target of an extra 400 µg/d will be effective, not only in lowering NTD risk, but also in optimizing homocysteine concentrations. Current evidence suggests that a fortification program based on providing an additional 200 µg folic acid/d would be highly effective in both cases, but confirmation of an optimal folic acid amount requires further investigation.
REFERENCES