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American Journal of Clinical Nutrition, Vol. 70, No. 2, 234-239, August 1999
© 1999 American Society for Clinical Nutrition

Original Research Communications

Fortification with low amounts of folic acid makes a significant difference in folate status in young women: implications for the prevention of neural tube defects1,2

Geraldine J Cuskelly, Helene McNulty and John M Scott

1 From the Northern Ireland Centre for Diet and Health, University of Ulster, Coleraine, Northern Ireland, United Kingdom, and the Department of Biochemistry, Trinity College, Dublin, Ireland.

2 Address reprint requests to H McNulty, Northern Ireland Centre for Diet and Health, University of Ulster, Coleraine, BT 52 1SA, Northern Ireland, United Kingdom. E-mail: H.McNulty{at}ulst.ac.uk.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 APPENDIX A
 REFERENCES
 
Background: Mandatory fortification of grain products with folic acid was introduced recently in the United States, a policy expected to result in a mean additional intake of 100 µg/d. One way of predicting the effectiveness of this measure is to determine the effect of removing a similar amount of folic acid as fortified food from the diets of young women who had been electively exposed to chronic fortification.

Objective: The objective was to examine the effect on folate status of foods fortified with low amounts of folic acid.

Design: We investigated the changes in dietary intakes and in red blood cell and serum concentrations of folate in response to removing folic acid–fortified foods for 12 wk from the diets of women who reportedly consumed such foods at least once weekly (consumers).

Results: Consumers (n = 21) had higher total folate intakes (P = 0.002) and red blood cell folate concentrations (P = 0.023) than nonconsumers (women who consumed folic acid–fortified foods less than once weekly; n = 30). Of greater interest, a 12-wk intervention involving the exclusion of these foods resulted in a decrease in folate intake of 78 ± 56 µg/d (P < 0.001), which was reflected in a significant reduction in red blood cell folate concentrations (P < 0.05).

Conclusions: Cessation of eating folic acid–fortified foods resulted in removing 78 µg folic acid/d from the diet. Over 12 wk this resulted in a lowering of red blood cell folate concentrations by 111 nmol/L (49 µg/L). This magnitude of change in folate status in women can be anticipated as a result of the new US fortification legislation and is predicted to have a significant, although not optimal, effect in preventing neural tube defects.

Key Words: Neural tube defects • folic acid • fortification • fortified food • breakfast cereals • women • reproduction • Northern Ireland


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 APPENDIX A
 REFERENCES
 
It is now accepted beyond any scientific doubt that folic acid protects against both recurrence (1) and first occurrence of neural tube defects (NTDs) (2). In response to this evidence, national committees worldwide have set almost identical folic acid recommendations for the prevention of NTDs (3–5). The recommendation of 4–5 mg folic acid/d to prevent NTD recurrences is clearly achievable only through supplementation. However, the prevention of first occurrences, which represent 95% of all NTD cases, is the more significant public health concern. To prevent first occurrences of NTDs, a folate intake of 400 µg folic acid/d is recommended (in addition to current intakes). Achievement of this recommended intake presents a particular challenge. Three options have been proposed by various committees: increased intakes of foods naturally rich in folate, use of folic acid supplements, and fortification of food with folic acid. Not only does the recommended daily intake of folate represent a 3-fold increase in current estimated intakes (6, 7), but even when a significant increase in food folates is achieved experimentally, it has been shown to be a relatively ineffective means of optimizing folate status in women compared with equivalent intakes of the vitamin from fortified food (8). Supplements appear to be highly effective in optimizing folate status in women who receive them experimentally (8), but the problem of compliance in the general target population (9) means that supplements are unlikely to be an effective means of primary prevention of NTDs. Thus, food fortification is seen by many as the only alternative likely to succeed.

Fortification of grain products with folic acid became a mandatory policy in the United States in January 1998 (10). Under the new policy, the amount of folic acid being added to every 100 g grain product is 140 µg. It is anticipated that this intervention will result in a mean additional intake of 100 µg folic acid/d in the target population, on the basis of dietary modeling and on the assumption of equal bioavailability (11). Elsewhere, the question of implementing a fortification policy for the primary prevention of NTDs is still under debate, 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. The amount of folic acid being added to the food supply under the new US folic acid fortification policy (100 µg/d) is almost certainly safe, but may be too low to prevent NTDs. In time, changes in the prevalence of NTDs in the United States will enable the true benefits of mandatory fortification with folic acid to be quantified, but it may be some time before such evidence becomes available. In the United Kingdom and certain other European countries, food fortification with folic acid is permitted currently on a voluntary basis, whereas some European countries do not allow fortification with any nutrient or expressly forbid the addition of folic acid to foods.

We showed previously that intervention with folic acid–fortified foods in nonconsumers of such foods is a highly effective means of optimizing folate status, resulting in a red blood cell folate response equal to that achieved with folic acid supplements (8). In that study we addressed the relative effectiveness of increased intakes of foods naturally rich in folate, folic acid supplements, and foods fortified with folic acid. However, the effect of habitual consumption of folic acid–fortified foods on folate status was not studied and, to our knowledge, remains uninvestigated.

The present investigation addressed whether folic acid–fortified foods have a significant effect on folate status in women and whether their exclusion in habitual consumers adversely affects folate status. We examined the contribution to folate status of foods fortified with low amounts of folic acid by investigating the changes in dietary intakes of folic acid and red blood cell and serum folate concentrations in response to the removal of folic acid–fortified foods from the diets of women for a 12-wk intervention period.


   SUBJECTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
RESULTS
 DISCUSSION
 APPENDIX A
 REFERENCES
 
Subject recruitment
Women aged 17–40 y were recruited in October 1993 from the staff and student populations of the University of Ulster, Northern Ireland. The study protocol was submitted to the University of Ulster Research Ethical Committee and was approved on the basis of UK Department of Health recommendations (3), which pertain in Northern Ireland, that women planning a pregnancy consume 400 µg folic acid/d in addition to current intakes. An exclusion criterion was therefore that subjects were neither pregnant nor planning a pregnancy. In addition, participants were instructed to withdraw from the study if at any time they suspected they were pregnant, however remote the possibility seemed, and to immediately start taking a folic acid supplement (0.4 mg/d) for 12 wk. Any mother of a child with an NTD, who had an NTD, or was a first-degree relative of someone with an NTD was also excluded. Other exclusion criteria included the use of folic acid or vitamin B-12 supplements, the use of medication (eg, anticonvulsants), or the existence of a chronic illness (eg, gastrointestinal disease) likely to interfere with folate metabolism. All participants gave informed, written consent. On completion of the study, participants were instructed to resume their usual diets and were given a free 12-wk supply of folic acid–fortified breakfast cereals.

Study design
The intervention was carried out over 12 wk. At baseline, habitual dietary intake was assessed, weight was measured, and blood samples were collected. On the day after collection of the baseline blood sample, subjects began the intervention, which consisted of an exclusion diet. Subjects were instructed both orally and in writing by a registered dietitian (GJC) to exclude folic acid–fortified foods from their diets for the 12-wk intervention period. To aid with compliance, subjects were given a comprehensive list of folic acid–fortified foods available in Northern Ireland at the time of the study (Appendix A). To ensure that nutrient intakes other than those from fortified foods were not altered, instructions were given to replace these foods with equivalent amounts of unfortified (isoenergetic) foods of similar composition. Dietary assessments were repeated during the intervention. A final blood sample was collected on completion of the intervention at week 12.

Laboratory assessment
Nonfasting venous blood samples (30 mL) were collected at baseline and after the 12-wk intervention. Samples were collected into non-heparin-containing integrated serum separator tubes for serum folate analysis and into EDTA-containing tubes for red blood cell folate and full blood count analyses. Serum samples were stored at -70°C until analyzed. Red blood cell hemolysates were prepared [ie, dilution (1:10) of whole blood with freshly prepared 1% ascorbic acid, mixed continuously for a minimum of 20 min] and stored at -70°C. Full blood counts were carried out on whole blood with an automated Coulter Counter (Causeway Health and Social Services Trust Laboratories, Coleraine, Northern Ireland). Serum and red blood cell folate concentrations were determined by using the microbiological assay on microtiter plates according to the method of O'Broin and Kelleher (12). Baseline and postexclusion blood samples were analyzed blind in one batch and within 6 mo after sampling.

Dietary assessment
Dietary intake was assessed at baseline and again at week 10–12 of intervention with the diet-history method (13) and with a self-administered food-frequency questionnaire (FFQ). All subjects were interviewed by a registered dietitian (GJC) during an open-ended interview lasting {approx}1 h. The interviewer emphasized that the information concerned usual dietary habits and not necessarily foods consumed in the previous week. Information was obtained from subjects about usual meal and snack patterns, the place of food consumption, foods typically consumed during the week and on weekends, methods of food preparation, and sizes of food portions. The FFQ, which focused on sources of food folate, was completed by subjects before the diet-history interview and was used to cross-check the information provided by the diet history. Any discrepancy between the information recorded in the FFQ and that from the diet history was discussed and clarified at interview. Food portion sizes were estimated by using standard household measures and published average portion sizes (14). Food intake data were analyzed for energy and nutrient intakes by using the dietary analysis program COMP-EAT 4 (Nutrition Systems, London). Subjects were classified as consumers (those who consumed folic acid–fortified foods at least once weekly) or nonconsumers (those who consumed folic acid–fortified foods less than once weekly).

Statistical analysis
Statistical analyses were carried out by using the SPSS program for WINDOWS (version 6.0; SPSS Inc, Chicago). Data were transformed before analysis as appropriate. Unpaired t tests were used to compare values between consumers and nonconsumers at baseline (preexclusion diet) and after the intervention ended (postexclusion diet) and the difference between the 2 values (postexclusion - preexclusion). Responses to intervention within each group were also assessed as the percentage changes between baseline and postexclusion values. P values < 0.05 were considered significant.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
DISCUSSION
 APPENDIX A
 REFERENCES
 
Initially, 57 women satisfying the necessary criteria for inclusion were recruited and classified as either consumers (n = 23; 40%) or nonconsumers (n = 34; 60%) of folic acid–fortified foods on the basis of their responses on the FFQs. Of these, 51 subjects (21 consumers and 30 nonconsumers) provided baseline blood samples and were included in the analysis. General subject characteristics of this sample are shown in Table 1Go. Consumers had significantly higher total folate intakes (265 ± 72 compared with 197 ± 71 µg/d; P = 0.002) and red blood cell folate concentrations (915 ± 250 and 776 ± 184 nmol/L, or 403 ± 110 and 342 ± 81 µg/L; P = 0.023) than nonconsumers, whereas differences in serum folate concentrations (17.9 ± 5.5 and 16.6 ± 7.5 nmol/L, or 7.9 ± 2.4 and 7.3 ± 3.3 µg/L, respectively) were not significant (data not shown). No subject in either group had a red blood cell or serum folate concentration below the normal reference range [340–2266 nmol/L (150–1000 µg/L) and 6.12–45.32 nmol/L (2.7–20 µg/L), respectively] at baseline.


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  		TABLE 1. Characteristics of consumers and nonconsumers of fortified foods1
 
Of the above baseline sample, a total of 48 subjects (20 consumers and 28 nonconsumers) provided a postexclusion blood sample and were considered to have completed the intervention study. Changes in folate intake and status of this sample in response to the exclusion of folic acid–fortified foods over the 12-wk intervention period are shown in Table 2Go. Subjects not included in the intervention analysis were those who failed to provide a postexclusion blood sample (n = 2) and those for whom the hematocrit value (required for the calculation of red blood cell folate concentrations) was not determined (n = 1). As a result of the exclusion of fortified foods, mean total folate intakes and red blood cell folate concentrations decreased significantly in consumers, but not in nonconsumers over the same time period. Differences in serum folate concentrations (postexclusion - preexclusion) were not significantly different between consumers and nonconsumers [5.4 nmol/L (2.42 µg/L) and 1.8 nmol/L (0.79 µg/L), respectively].


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  		TABLE 2. Changes in folate intake and status in consumers and nonconsumers of fortified foods in response to the exclusion of folic acid–fortified foods for 12 wk1
 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
APPENDIX A
 REFERENCES
 
Fortification with folic acid, recently (1998) introduced as a mandatory policy in the United States (10), is seen by many as the only means likely to be effective in the primary prevention of NTDs, but the issue is controversial. There are those who are concerned about the safety of chronic fortification with folic acid, particularly the possibility, although not proven, that pernicious anemia could be masked, thereby preventing a timely diagnosis of vitamin B-12 deficiency (15). The alternative view is that the new US fortification legislation has not gone far enough and that higher intakes of folic acid than those being delivered are safe and would give greater protection against NTDs (16, 17). Safety concerns have, however, resulted in the decision in the United States to fortify at low levels, which almost certainly carry no risk but may be ineffective in preventing NTDs.

In Northern Ireland, a country in which food fortification with folic acid is voluntary, the current investigation showed that the habitual consumption of foods fortified with low amounts of folic acid is associated with a mean dietary intake of the vitamin that is 35% higher than that of nonconsumers, which in turn is reflected in significantly higher red blood cell folate concentrations in consumers than in nonconsumers: 915 and 776 nmol/L (403 and 342 µg/L). Although our objective in the present study was to examine the effects of both consumption and nonconsumption of foods fortified with folic acid, in effect we examined the effects of consumption and nonconsumption of fortified breakfast cereals because we found these to be the only folic acid–fortified foods being consumed by our subjects at the time of the investigation.

Our findings are in good agreement with those of Schorah and Wild (18), who reported the effects of the introduction of folic acid–fortified foods in young women by measuring their total folate intakes from 1986 to 1988, a period during which breakfast cereals were being fortified with folic acid for the first time in the United Kingdom. These authors estimated the total folate intake to be 43% higher in consumers (n = 10) than in nonconsumers (n = 14) of fortified breakfast cereals. In a small number of consumers (n = 4) in whom intakes were assessed before and after folic acid fortification, the increase in intake was estimated to be 54%. Unlike in the present investigation, the effects of fortification on hematologic folate status were not reported in this previous study.

Interpretation of our baseline (observational) data was confounded by the possibility that apparent differences in folate intake and status between the 2 groups may have been influenced by other dietary or lifestyle practices of the participants, whose habitual diet happened to include fortified foods. For example, there was a much higher percentage of smokers in the nonconsumer group than in the consumer group, and this may have contributed to the lower folate status of the nonconsumers, consistent with previous reports of lower folate status among smokers than among nonsmokers (19). However, when fortified breakfast cereals were excluded from the diet of the consumer group in the present study, the resultant data showed clearly that folic acid fortification had made a significant contribution to their folate status. The exclusion of folic acid–fortified foods from the diets for 12 wk caused significantly greater reductions in total folate intakes and red blood cell folate concentrations in consumers than in nonconsumers (27% compared with 4%; 12% compared with 1%, respectively), whereas the decrease in serum folate concentrations was not significantly different between the consumers (28%) and nonconsumers (7%). Energy intakes did not change significantly in either group after folic acid–fortified foods were excluded, suggesting that subjects had (as advised) replaced fortified foods with isoenergetic foods.

The 12-wk duration of the present study likely underestimated the effect of folic acid fortification on red blood cell folate concentrations because folic acid supplied as part of a food fortification program would be supplied continuously, ie, longer than 12 wk. In addition, the difference of 78 µg in the daily folic acid intake was somewhat lower than the predicted extra intake of 100 µg/d as a result of the new US folic acid fortification legislation. For these reasons, the change in folate status resulting from folic acid fortification in the present study was probably an underestimate of the effect on folate status that can be expected in American women as a result of the new US folic acid fortification legislation.

The magnitude of change in red blood cell folate status as a result of fortification shown in this investigation has implications for public health efforts to reduce the risk of NTDs. NTD risk has been shown to be associated with maternal red blood cell folate concentrations in a continuous dose-response inverse relation by Daly et al (20), who showed a >8-fold difference in risk between women with red blood cell concentrations <341 nmol/L (150 µg/L) and those with concentrations >=908 nmol/L (400 µg/L). The 78-µg/d reduction in folic acid intake as a result of the exclusion of folic acid–fortified foods from the womens' diets caused a significant decrease in red blood cell folate concentrations of 111 nmol/L (49 µg/L). The model of Daly et al (20) shows substantial decreases in NTD risk as red blood cell folate concentrations increase: estimated risks of 6.6, 3.2 , 2.3, and 1.6/1000 births for women with red blood cell folate concentrations of <338, 341–452, 454–679, and 681–906 nmol/L (<149, 150–199, 200–299, and 300–399 µg/L) in early pregnancy. Thus, a mean increase of 111 nmol/L (49 µg/L) in red blood cell folate concentrations, shown in this study to be possible through an increased folate intake of <100 µg folic acid/d via folic acid–fortified food, could decrease the NTD risk by as much as 50% in those women with the lowest folate status, although most cases of NTD occur in women with a higher folate status (20). Higher amounts of folic acid would be predicted to have a greater effect, so clearly this amount could not be considered to be optimal in preventing NTDs.

Current recommendations in the United States and elsewhere advise an extra 400 µg folic acid/d for the prevention of the first occurrence of an NTD and should remain the target optimal intake in the absence of unequivocal evidence that a lower intake provides equal protection. However, the present study suggests that a mandatory policy delivering as little as an extra 100 µg folic acid/d at a population level could make a valuable contribution to reducing the incidence of NTDs. This population measure, in addition to public health messages targeted specifically at women during their reproductive years to increase their folate intakes, should prove far more effective than public health messages alone. Although mandatory fortification of food with high amounts of folic acid might be most effective, the reality for the foreseeable future is that governments will choose lower amounts, making this study very relevant.

A recent intervention study (21) to determine the minimum effective supplemental dose of folic acid required to increase red blood cell folate to concentrations that appear to be protective against NTDs predicted a 22% reduced risk of NTDs as a result of the projected 100-µg/d increase of folate in the US diet as a result of the recently instituted fortification policy. A subsequent reevaluation of this study predicted the relative risk reduction to be 18% (22). However, such predictions are based on the assumption that fortified foods will be as effective in increasing folate status as were the supplements used in the investigation. This assumption would also have formed the basis of the US Food and Drug Administration's decision to fortify at the amount of folic acid it chose (10). Recent evidence from bioavailability studies using a stable-isotope protocol (23) and from studies of red blood cell folate concentrations before and after a 3-mo feeding trial with folate (8) suggests that this assumption is likely to be valid. Nevertheless, there is at least some earlier evidence to the contrary, suggesting a considerably lower bioavailability of folic acid from fortified maize or rice (24) or bread (25) than from the vitamin in its free form. However, the present study provides further evidence that food fortification with folic acid is a highly effective means of increasing folate status.

In summary, the present study suggests that an extra 100 µg folic acid/d will have a significant beneficial effect on red blood cell folate status in women. Furthermore, the results indicate that providing the vitamin via fortified food will be an effective means of delivering this dose. Thus, the new folic acid fortification legislation in the United States can be expected to result in a significant increase in the baseline folate status of the population, which should in turn produce an important reduction in the incidence of NTDs. This population-wide strategy will not, however, prevent all preventable NTDs. Efforts should still continue in the United States and elsewhere to target women of reproductive age to increase their folic acid intakes so that they will achieve optimal folate status for the prevention of NTDs.


   APPENDIX A
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 APPENDIX A
REFERENCES
 
Instructions for participants regarding the exclusion of folic acid–fortified foods from their diets
For the next 3 mo, ie, until your next blood sample is taken, you are required to

  1. avoid folic acid supplements or multivitamin preparations containing folic acid, and
  2. avoid folic acid–fortified breakfast cereals and other foods in the "foods to avoid list" below.

Please replace these items with foods in the "foods allowed list" below.

FOODS TO AVOID LIST

FOODS ALLOWED LIST

Please note: At present, breads and milk purchased in Northern Ireland are not fortified with folic acid, so these are allowed. You will be informed if food items not already on the "foods to avoid list" become fortified with folic acid during the study period.

Apart from the above requirements, please continue to eat your usual diet until your next blood sample is drawn.


   ACKNOWLEDGMENTS
 
We thank Fiona McCullough for her assistance in subject recruitment and dietary analysis.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 APPENDIX A
 REFERENCES
 

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  12. O'Broin S, Kelleher B. Microbiological assay on microtitre plates of folate in serum and red cells. J Clin Pathol 1992;45:344–7.[Abstract/Free Full Text]
  13. Burke BS. The dietary history as a tool in research. J Am Diet Assoc 1947;23:1041–6.
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  23. Pfeiffer CM, Rogers LM, Bailey LB, Gregory JF III. Absorption of folate from fortified cereal-grain products and of supplemental folate consumed with or without food determined by using a dual-label stable-isotope protocol. Am J Clin Nutr 1997;66:1388–97.[Abstract/Free Full Text]
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Received for publication August 20, 1998. Accepted for publication January 22, 1999.




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