Abstract
To reduce neural tube defects (NTDs), the U.S. Food and Drug Administration (FDA) mandated that by January 1998 all enriched grain products should contain 140 μg of folic acid (FA)/100 g of flour. Groups concerned with optimal prevention of NTDs had argued that the level should be 350 μg/100 g. However, when it appeared that the debate might delay implementation of any fortification, these groups petitioned the FDA to implement fortification at the originally proposed level of 140 μg/100 g, anticipating that the FDA might consider increasing the level at a later time. Mandated FA fortification (FAF) has now been in place in the United States for 9 y. The impact of this important public health intervention on NTD rates, the possible benefit to other disease conditions, and potential harms have been evaluated. As background for a possible request that the FDA consider increasing FAF, evidence bearing on the question of whether an increase can further reduce NTD births without causing harm is reviewed here. The published data indicate that it is appropriate that the FDA conduct or commission a balanced analysis of the evidence by scientists who will act on that evidence to decide this important question.
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Main
Neural tube defects (NTDs) result from failure of normal neural tube closure by approximately 28 d after conception, before most women know they are pregnant. In 1991, the British Medical Research Council (MRC) Vitamin Study, a randomized controlled trial (RCT), showed that administration of folic acid (FA), 4000 μg/d before pregnancy, could reduce by 72% the recurrence of NTDs in women with a prior NTD pregnancy (1). The MRC has identified this report as one of its most influential (2). A second RCT showed that a multivitamin with FA could prevent the first occurrence of NTDs (3).
On the basis of the available evidence, the U.S. Public Health Service recommended in 1992 that all women of childbearing age consume at least 400 μg of synthetic FA/d (4). In spite of continuing efforts by the Centers for Disease Control and Prevention (CDC), the March of Dimes, and others to encourage adherence to this recommendation, regular Gallup surveys have indicated that the fraction of nonpregnant women 18–45 y old who regularly take a FA supplement has remained at approximately 30% over the last decade (5). Moreover, in annual examinations of women of reproductive age in the United States, the physician discusses the importance of FA intake only about half the time, and about half of all pregnancies are unplanned (6).
To increase FA intake among women of childbearing potential, the U.S. Food and Drug Administration (FDA) mandated that by January 1998, FA should be added to all “enriched” cereal-grain products at a level of 140 μg/100 g of flour (7). The FDA's compulsory fortification with FA has been praised as possibly "the most important science-driven intervention in nutrition and public health in decades” (8).
During the period of scientific review that preceded the FDA's decision, the CDC, American Medical Association (AMA), American Academy of Pediatrics (AAP), American College of Obstetricians and Gynecologists (ACOG), American College of Medical Genetics (ACMG), March of Dimes, and Spina Bifida Association had argued for a higher level of fortification (350 μg/100 g) on the basis of models that predicted that the mandated dose would reduce the rate of NTDs by only 20% (7,9,10). However, when it appeared that the fortification initiative was stalled over this debate, the AAP, ACOG, ACMG, and March of Dimes petitioned the FDA to ratify the proposed level of 140 μg/100 g, with the anticipation that the FDA would review the possibility of increasing fortification in the future.
This article reviews current evidence related to the potential benefits and harms of increasing FA fortification (FAF) as a background for considering whether it is appropriate now to petition the FDA to address scientifically the question of the optimal safe level of FAF. The information contained here might also inform deliberations in other countries considering the implementation of FAF.
EFFECT OF FAF ON RATES OF NTDS
A CDC analysis of births from 23 states and Puerto Rico compared NTD rates before and after FAF (11). The prevalence of NTDs was reduced by 26% in programs without prenatal diagnosis and by 27% in programs that included data from all NTD-affected pregnancies (live births, still births, fetal deaths, and elective terminations) (11). The reduction in NTD rates in Canada, which instituted FAF at 150 μg/100 g in 1998, have varied by province from 32% to 78%, and the higher the prefortification NTD level, the greater the reduction (12). In pooled data from seven Canadian provinces, FAF has resulted in reduction in NTD-affected pregnancies by 46% (from 1.58/1000 births to 0.86/1000 births) (12).
FAF in the United States has been estimated to avert $145 million/y in costs for the care of children born with spina bifida and to produce a net economic benefit of $422 million/y (2002 dollars) (13). The prevalence of NTDs in European countries that have depended on education to promote the use of FA supplements rather than FAF has not clearly declined (14,15).
The somewhat greater than predicted reduction in NTD prevalence in the Untied States because of fortification is reflected in the early reports of plasma and blood cell folate levels (16). These levels were estimated to reflect an increase in the average daily FA intake of approximately 200 μg, twice the intake originally projected (7,9,10,17).
The reason for these higher than expected folate concentrations and rates of NTD prevention is not clear, but a 1999 survey of fortified products identified higher than mandated levels in several products (18). In addition, FA has been voluntarily added to a variety of other foods. On the other hand, two recent analyses of National Health and Nutrition Examination Survey (NHANES) data (19,20), one of which used a correction for the usual measurement error inherent in dietary intake surveys (19), indicate that folate intake has increased by 100–130 μg/d after fortification, as predicted. In addition, a recent comparison of NHANES data on women of childbearing age found that serum and erythrocyte folate levels fell 16% and 8%, respectively, from 1999 to 2000 to 2003 to 2004 (21). Perhaps related is the report that the folate content of several breads was reduced during 2000–2003 (22).
In 2000, Chile required fortification of the wheat flour used for bread with FA at 220 μg/100 g (23). Chilean women eat about twice as much bread as do American women, and this level was chosen to increase FA consumption by an average of 400 μg/d. Rates of NTD live and still births after fortification decreased by 43%, and the overall stillbirth rate decreased by 20% (24,25). Unregistered induced abortions are uncommon in this population (26). FAF of wheat flour in 1997 and corn flour in 1999 reduced NTD births by 35% in Costa Rica (27).
OTHER POSSIBLE BENEFITS OF FAF
Evidence that FA can prevent NTDs is considered convincing. The near elimination since mandated fortification of the low blood folate levels associated with anemia (16) makes folate deficiency anemia unlikely in the United States, an important health benefit for individuals across the general population. However, evidence that FA has other health effects has not received general acceptance.
Vascular disease.
Attention has focused particularly on the relationship between FA intake, homocysteine, and vascular disease, stimulated by the report of McCully (28) in 1969 that individuals with the metabolic disorder homocystinuria die early in life from severe atherosclerosis. Meta-analyses of association studies have concluded that elevated homocysteine is an independent risk factor for cardiovascular disease (CVD) and stroke (29–32).
Attempts to understand the underlying mechanism indicate that homocysteine has a direct effect on endothelial structure and function (33,34). Raising blood folate lowers blood homocysteine and reduces markers of oxidant stress and inflammation (34). FA can also directly correct endothelial dysfunction in type-1 or type-2 diabetes, coronary artery disease, and other disorders exclusive of its homocysteine-lowering effect (35–37).
Population homocysteine levels (16,38) and deaths caused by stroke in the United States and Canada (39) have declined significantly since the advent of FAF. There are abundant data that associate lower population homocysteine levels and greater FA intake with protection against CVD and stroke (29–32,40). Three large RCTs have examined the effect of lowering homocysteine with large doses of FA in combination with B6 or B12, or both, on further vascular events in individuals with a history of acute myocardial infarction, stroke, vascular disease, or diabetes (41–43). One of these trials reported marginally significant protection against stroke (43), but none of the three showed protection against other CVDs, and one trial showed a trend (not significant) toward more myocardial infarctions (42). Median follow-up periods were 24, 40, and 60 mo. A meta-analysis of RCTs that studied the effect of FA supplementation on prevention of CVDs in persons with preexisting cardiovascular or renal disease also did not show a preventive effect (44).
Possible explanations for the discordant results between the observational studies and trials include the greater risk of confounding factors in the former; the possibility that the RCTs lack the statistical power to detect the expected 10–20% reduction in cardiovascular endpoints because of the wide availability of fortified foods; or the difference between observing the effects of primary prevention in the early stages of the disease process and attempts to intervene after demonstrated vascular damage (33,38,43–46).
Other birth defects.
The balance of available data, including a recent meta-analysis, strongly supports the conclusion that periconceptional use of multivitamins containing FA can reduce the risk of certain birth defects other than NTDs, especially congenital cardiac anomalies, orofacial clefts, and combined birth defects exclusive of NTDs (3,47–52). Orofacial clefts have not declined since the introduction of fortification in Chile (26), but mandated fortification in the United States has been associated with modest yet statistically significant decreases in several birth defects (52). Higher levels of FA than those achieved by fortification or the inclusion of other vitamins may be needed to prevent other birth defects optimally (47).
Cognitive decline.
Elevated plasma homocysteine, low blood folate, or low folate intake has been associated in several large studies, including a recent RCT (53), with more rapid cognitive decline and increased rates of dementia and Alzheimer disease in the elderly (53–59). This relationship has not been consistent, however (60–62).
Summary.
RCTs, as designed and conducted to date, have not shown clear and consistent proof that increasing FA consumption can prevent more than NTDs. However, there are strong observational and some RCT data that support additional health benefits from FA, and the question of other salutary effects of FA is far from settled (46).
IS THERE EVIDENCE THAT FA CAUSES ADVERSE EFFECTS?
At the time FAF was mandated, no additional funding was made available for the systematic study of possible adverse effects (8). Nevertheless, data on safety have emerged.
In establishing new recommendations for dietary folate intake in 1998, the Institute of Medicine (IOM) Food and Nutrition Board set its tolerable upper level of synthetic FA at 1000 μg/d on the basis of the risk that high FA intake could correct the anemia of pernicious anemia and thus “mask” the diagnosis yet permit or promote neurologic damage (63). In the absence of controlled, dose-response data, the lowest-observed adverse effect level (LOAEL) was fixed at 5000 μg/d based on case reports from 1947 to 1960 in which neurologic manifestations progressed on high-dose folate therapy. The relatively high uncertainty factor of 5 was then applied to the LOAEL to derive the figure of 1000 μg (63). The issue of high-dose folate therapy in patients with pernicious anemia is reviewed in 64.
In 1573 adults with abnormally low B12 levels, the proportion of subjects with B12 deficiency but no anemia before FAF (39.2%) did not differ from that after fortification (37.6%) (65). Other evidence also favors the conclusion that FA in doses currently consumed does not cure the anemia of B12 deficiency (reviewed in 62). NHANES data indicate that the percentage of U.S. adults over 64 y who consume more than 1000 μg folate/d has increased since fortification but has remained below 5% in all groups (19).
No adverse effects were demonstrated in the many studies that evaluated the periconceptional use of FA in doses of up to 5000 μg/d (1) or in the recently completed homocysteine-lowering RCTs in which daily folic FA doses were 800–2500 μg (34,41–43). The periconceptional studies were generally not designed to assess adverse effects, but such effects were specifically addressed in the trials.
CONCERNS ABOUT POSSIBLE ADVERSE EFFECTS OF FAF
Masking B12 deficiency.
In setting the tolerable upper level for synthetic FA intake at 1000 μg/d for adults, the IOM Food and Nutrition Board evaluated all potential hazards associated with high folate intake and found reason for concern only on the issue of masking B12 deficiency and consequent neurologic damage (63). This concern continues to be the major reason offered for delaying fortification, although no evidence has emerged to demonstrate that the fear is justified.
Intake in children.
Concern has been expressed that children are likely exceeding the IOM's age-related tolerable upper level for FA since the advent of fortification. The IOM found no data to suggest that other life-stage groups are more susceptible to the adverse effects of high folate intake than adults, and lacking utilization and metabolic turnover data, upper levels for children were adjusted down on the basis of relative body weight (63). The 1000 μg adult limit, established because of the concern for exacerbating neuropathy, was used as the starting point, although this risk in children is negligible. In consideration of the rapid growth that characterizes childhood, it is possible that relatively higher doses of FA would be beneficial.
Unmetabolized FA.
Related to this concern are reports that unmetabolized FA, not the natural form of folate, appeared in the circulation after ingestion of 800 μg FA/d given as fortified breakfast cereal and bread or as 300–400 μg given in a single dose (66), or in cord blood from 11 infants born to Irish mothers (67). The 11 mothers had not consumed FA supplements, but some foods are fortified with FA in Ireland. The authors assumed that the circulating unmetabolized FA represents excess that could harm the baby.
FA is converted to its physiologic form in tissues, and excess folates are excreted (68). It is not known what harm, if any, circulating unmetabolized FA might cause. Surveys since 1980 indicate that approximately one quarter of adults in the United States regularly consume a multivitamin containing FA (69,70). Moreover, almost all pregnant women in the United States consume prenatal vitamins that contain 600–800 μg of FA, and some consume additional FA supplements of several milligrams (71). Thus, it is likely that most American infants born within recent decades have had unmetabolized FA circulating at birth and that many Americans have had unmetabolized FA circulating for years. No untoward effects of this condition have been suggested.
Decreased natural killer cell activity.
In a group of 109 overweight or obese women, those with higher levels of circulating unmetabolized FA had 23% lower natural killer (NK) cell activity than did women with lower levels (72). It is not clear that a drop in NK cell activity of this magnitude has biologic meaning. The authors raise the possibility that such a decline could compromise host defense, but NK cell activity is particularly sensitive to up-regulation by inflammatory cytokines (73), and lower activity could reflect less inflammation.
Cancer promotion.
Folate is required for one-carbon transfer (methylation) reactions, including those involved in the biosynthesis of DNA and RNA. Folate deficiency in humans leads to DNA strand breaks, known to predispose to cancer, and these can be corrected by increasing FA intake (74). The available epidemiologic data collectively support the concept that higher folate status offers relative protection against several cancers, including colorectal, cervical, and breast, and leukemia (75). Preconception and prenatal vitamin use has been reported to reduce the risk in offspring of brain tumors, neuroblastoma, and leukemia by 30–60% (76–79); infant neuroblastoma in Ontario has decreased by 60% since the introduction of FAF (80).
On the other hand, folate antagonists such as methotrexate (MTX) inhibit the rapidly dividing malignant cells of established tumors, which has led to the concern that dose and timing of folate intervention might determine whether folate prevents or promotes cancer (reviewed in 81–83). In two mouse models of spontaneously developing intestinal adenomas, folate supplementation at doses four to 10 times above basal requirements suppressed or enhanced the development of adenomas depending on whether folate was given before or after adenoma foci were established (84,85). However, the results differed with the two mouse strains, the mice were genetically programmed to develop adenomas, and the FA doses were comparably higher than those to which North Americans would be regularly exposed even if taking a FA supplement. In an RCT of individuals with a recent history of colorectal adenomas, FA, 1000 μg/d, was associated with a higher risk of having three or more adenomas at the 6–8-y follow-up (75), in agreement with the concerns raised in adenoma-prone mice.
Epigenetic hypermethylation.
Folate's role in methylation reactions has also raised concern that increasing blood folate could increase the methylation of DNA cytosine residues that control promoter activity. This “epigenetic” hypermethylation could silence promoter activity and thereby inactivate tumor-suppressor genes or genes that play a role in cell-cycle control, repair of DNA damage, or other functions that constrain carcinogenesis (82). Humans given FA, 5000–10,000 μg/d for 3–12 mo, had increased methylation of genomic DNA (genes not identified) in resected adenomas (reviewed in 82), and adults given 400 μg of FA/d for 10 wk had increased methylation in leukocytes of 31% (86). On the other hand, FA, 2000 μg/d for 6 mo did not modulate genomic DNA methylation in lymphocytes from healthy adults (82).
In a mouse strain carrying the abnormal agouti gene for coat color, dams fed a diet containing four added methyl donors and cofactors, one of which was FA, delivered offspring with hypermethylation of the agouti gene and a change in coat color (87). This experiment demonstrates the biologic principle that diet during pregnancy can modify the phenotype of the offspring, at least under certain circumstances; but its relevance to humans and human disease is uncertain. In summary, there is no conclusive evidence at this time that FA intake at levels expected with fortification and supplements can cause meaningful epigenetic changes in humans.
Interference with antifolate treatment.
Concern has been raised that FAF could interfere with the therapeutic effect of antifolates such as MTX on malignant and inflammatory diseases. However, MTX is used over wide dose ranges, and dosage is carefully tailored to each individual patient because of its potential for serious toxicity (88). In the event of such, some form of folate is given parenterally in doses much higher than those available through fortification and supplements (88). FA supplements (commonly 1000 μg/d) are routinely given along with MTX to prevent or treat toxicity (89), to reduce toxicity-related discontinuation of MTX in rheumatoid arthritis (90), and to allow effective use of MTX to involute ectopic fetuses (91). It appears unlikely that fortification at present or higher levels can adversely affect the application or efficacy of antifolate therapy.
The antiseizure medication phenytoin and folates interact bidirectionally, and either can reduce the circulating level of the other, raising concern that fortification could lead to poorer seizure control. Again, however, dosages are individualized across a range to obtain optimal seizure management. Moreover, blood phenytoin levels in a large Canadian sample were not changed by FAF (92).
Multiple births and miscarriages.
Early studies suggested that periconceptional multivitamin use was associated with a higher prevalence of multiple births and miscarriages, but confounding by older maternal age, ovarian stimulation, assisted reproduction, or previous miscarriage was not eliminated (reviewed in 51). Consumption of 4000 μg/d FA with or without other vitamins in the MRC RCT (1), or as FA alone, 400 μg/d, in the 250,000-subject China-US Collaborative Project (93–95) was not associated with an increased risk of multiple births or miscarriages. In one study, low blood folates were associated with increased risk of miscarriage, but normal levels were not (96). Twinning rates have not been affected by mandated fortification in the United States (97–101) or Chile (25). Higher blood folates were associated with better embryo survival in multiple embryo transfer but not with rates of natural twinning (102).
Summary.
It is vitally important to consider possible risks of FAF at any level, and this should be an ongoing process (17). However, the evidence available to date does not support the conclusion that foods fortified with FA or FA supplements cause harm.
COULD HIGHER LEVELS OF FAF PREVENT MORE NTDS?
Inherent in the question of the optimal level of FAF is the question of the percentage of NTDs that can be prevented with periconceptional FA at any dose. It has been assumed that the majority of NTDs are caused by dietary folate deficiency, but other causes of NTDs are recognized. It is possible that some of these can be prevented by FA at doses currently recommended or higher (103).
The MRC Vitamin Study had sufficient cases to estimate the magnitude of the preventive effect of a specific dose of FA. In the main analysis based on all women randomized, including 7% of the total who had stopped taking their pills before they became pregnant, the rate of prevention was 72% (1). That figure has commonly been taken as a lower boundary to the preventable fraction in a typical Western population. If the analysis was restricted to women who took their pills and were not already pregnant at the time of randomization (80% of the total sample), the rate of prevention was 83% (1). In the large China-US study, consumption of 400 μg/d FA reduced NTD births by 79% in a northern region where NTD rates were high and by 41% in a southern region where the rates were lower (93).
A two-stage model based on published evidence has been developed to analyze the relationship between prevention of NTDs and FA intake in doses relevant to fortification (10). Data were used from 13 publications that reported the effect on serum folate of consumption of FA doses of up to 1000 μg/d. A given rise in FA intake was associated with a constant rise in serum folate from any starting concentration. In the second step, data from a large cohort study (104) were plotted to compare serum folate levels and risk of NTDs. The plotted association indicated a constant proportional relationship between serum folate and risk. According to the model, prevention of NTDs increases in a dose-responsive fashion as intake of FA increases.
Mandated fortification has been associated with a reduction in the NTD rate of 27% in U.S. programs that surveyed all NTD-affected pregnancies (live births, still births, fetal deaths, and elective terminations) and with a reduction of 26% in programs without prenatal ascertainment (11). Reductions have varied from 32 to 54% in various Canadian provinces, except in Newfoundland, where prefortification NTD rates were exceptionally high and prevention was 78% (12). Most Canadian provinces surveyed all NTD pregnancies as well as NTD births. The decrease in Chile was 43% (23,24). Whether the study analyzed the preventive effect of supplements or fortification, the higher the baseline NTD rate, the higher the percentage of cases prevented.
The reduction in NTD rates attained by fortification to date, 27% in the United States (11), is well below the evidence-based projected achievable level (105), and the available data support the conclusion that increasing FAF would further reduce NTDs. More effort will be needed to achieve the 2010 national health objective of reducing NTDs by 50% (105). In agreement with this concept, the AMA recommended in 2006 that the FDA be urged to increase FAF to 350 μg/100 g of grain (106).
CONCLUSIONS
The possibility that higher FA intake may pose a risk to the general population must be taken seriously. The risks that have been postulated carry varying degrees of biologic plausibility, and these should be explored; but, at present, these risks are theoretical. It will not be possible to prove the negative in this case that increasing FAF will never cause harm. However, there is no known evidence that consumption of FA through dietary supplements and fortification as available in the United States has harmed individuals in any age group. The question of whether to add more FA to fortified grains is too important to public health to remain unexamined. It is imperative that the FDA convene or commission the convening of a review body that will evaluate the evidence and use that evidence to decide on this important question.
Abbreviations
- CVD:
-
cardiovascular disease
- FA:
-
folic acid
- FAF:
-
folic acid fortification
- MTX:
-
methotrexate
- NHANES:
-
National Health and Nutrition Examination Survey
- NTD:
-
neural tube defect
- RCT:
-
randomized controlled trial
References
1991 Prevention of neural tube defects: results of the Medical Research Council Vitamin Study. MRC Vitamin Study Research Group. Lancet 338: 131–137
Blakemore C, Davidson J 2006 Putting a value on medical research. Lancet 367: 1293–1295
Czeizel AE, Dudas I 1992 Prevention of the first occurrence of neural-tube defects by periconceptional vitamin supplementation. N Engl J Med 327: 1832–1835
Centers for Disease Control 1992 Recommendations for the use of folic acid to reduce the number of cases of spina bifida and other neural tube defects. MMWR Morb Mortal Wkly Rep 41: 1–7
March of Dimes 2005 Folic acid and the Prevention of Birth Defects: A National Survey of Pre-Pregnancy Awareness and Behavior among Women of Child-Bearing Age, 1995–2005. March of Dimes, White Plains, NY
March of Dimes and Centers for Disease Control and Prevention 2005 Nationwide Healthcare Practitioner Survey on Folic Acid and B12 Knowledge and Practice. March of Dimes, White Plains, NY
US Food and Drug Administration 1996 Food standards: amendments of standards of identity for enriched grain products to require addition of folic acid. Fed Regist 61: 8781–8797
Rosenberg IH 2005 Science-based micronutrient fortification: which nutrients, how much, and how to know?. Am J Clin Nutr 82: 279–280
Daly S, Mills JL, Molloy AM, Conley M, Lee YJ, Kirke PN, Weir DG, Scott JM 1997 Minimum effective dose of folic acid for food fortification to prevent neural-tube defects. Lancet 350: 1666–1669
Wald NJ, Law MR, Morris JK, Wald DS 2001 Quantifying the effect of folic acid. Lancet 358: 2069–2073
Centers for Disease Control and Prevention 2004 Spina bifida and anencephaly before and after folic acid mandate, United States, 1995–1996 and 1999–2000. MMWR Morb Mortal Wkly Rep 53: 362–365
De Wals P, Tairou F, Van Allen MI, Uh S-H, Lowry RB, Sibbald B, Evans JA, Van den Hof MC, Zimmer P, Crowley M, Fernandez B, Lee NS, Niyonsenga T 2007 Reduction in neural-tube defects after folic acid fortification in Canada. N Engl J Med 357: 135–142
Grosse SD, Waltzman NJ, Romano PS, Mulinare J 2005 Reevaluating the benefits of folic acid fortification in the United States: economic analysis, regulation, and public health. Am J Public Health 95: 1917–1922
Cornel MC, de Smit DJ, de Jong-van den Berg LT 2005 Folic acid: the scientific debate as a base for public health policy. Reprod Toxicol 20: 411–415
Eichholzer M, Tönz O, Zimmermann R 2006 Folic acid: a public-health challenge. Lancet 367: 1352–1361
Pfeiffer CM, Caudill SP, Gunter EW, Osterloh J, Sampson EJ 2005 Biochemical indicators of B vitamin status in the US population after folic acid fortification: results from the National Health and Nutrition Examination Survey 1999–2000. Am J Clin Nutr 82: 442–450
Yetley EA, Rader JI 2004 Modeling the level of fortification and post-fortification assessments: U.S. experience. Nutr Rev 62: S50–S59
Rader JI, Weaver CM, Angyal G 2000 Total folate in enriched cereal-grain products in the United States following fortification. Food Chem 70: 275–289
Bentley TG, Willett WC, Weinstein MC, Kuntz KM 2006 Population-level changes in folate intake by age, gender, and race/ethnicity after folic acid fortification. Am J Public Health 96: 2040–2047
Yang Q-H, Carter HK, Mulinare J, Berry RJ, Friedman JM, Erickson JD 2007 Race-ethnicity differences in folic acid intake in women of childbearing age in the United States after folic acid fortification: findings from the National Health and Nutrition Examination Survey, 2001–2002. Am J Clin Nutr 85: 1409–1416
Boulet SL, Yang Q, Mai C, Mulinare J, Pfeiffer CM 2007 Folate status in women of childbearing age, by race/ethnicity: United States, 1999–2000, 2001–2002, 2003-2004. MMWR Morb Mortal Wkly Rep 55: 1377–1380
Johnston KE, Tamura T 2004 Folate content in commercial white and whole wheat sandwich breads. J Agric Food Chem 52: 6338–6340
Hertrampf E, Cortés F, Erickson JD, Cayazzo M, Freire W, Bailey LB, Howson C, Kanwell GP, Pfeiffer C 2003 Consumption of folic acid-fortified bread improves folate status in women of reproductive age in Chile. J Nutr 133: 3166–3169
Hertrampf E, Cortes F 2004 Folic acid fortification of wheat flour: Chile. Nutr Rev 62: S44–S49
Hertrampf E 2005 National Food Fortification Program with Folic Acid in Chile. Technical Consultation on Folate and Vitamin B12 Deficiencies. World Health Organization, Geneva
Castilla EE, Orioli IM, Lopez-Camelo JS, Dutra Mda G, Nazer-Herrera J, Latin American Collaborative Study of Congenital Malformations (ECLAMC) 2003 preliminary data on changes in neural tube defect prevalence rates after folic acid fortification in South America. Am J Med Genet A 123: 123–128
Chen LT, Rivera MA 2004 The Costa Rican experience: reduction of neural tube defects following food fortification programs. Nutr Rev 62: S40–S43
McCully KS 1969 Vascular pathology of homocyst(e)inemia: implications for the pathogenesis of arteriosclerosis. Am J Pathol 56: 111–128
Homocysteine Studies Collaboration 2002 Homocysteine and risk of ischemic heart disease and stroke: a meta-analysis. JAMA 288: 2015–2022
Wald DS, Law M, Morris JK 2002 Homocysteine and cardiovascular disease: evidence on causality from a meta-analysis. BMJ 325: 1202–1206
Cronin S, Furie KL, Kelly PJ 2005 Dose-related association of MTHFR 677T allele with risk of ischemic stroke: evidence from a cumulative meta-analysis. Stroke 36: 1581–1587
Casas JP, Bautista LE, Smeeth L, Sharma P, Hingorani AD 2005 Homocysteine and stroke: evidence on a causal link from mendelian randomisation. Lancet 365: 224–232
Lentz SR, Sobey CG, Piegors DJ, Bhopatkar MY, Faraci FM, Malinow MR, Heistad DD 1996 Vascular dysfunction in monkeys with diet-induced hyperhomocyst(e) inemia. J Clin Invest 98: 24–29
Loscalzo J 2006 Homocysteine trials: clear outcomes for complex reasons. N Engl J Med 354: 1629–1632
MacKenzie KE, Wiltshire EJ, Gent R, Hirte C, Piotto L, Couper JJ 2006 Folate and vitamin B6 rapidly normalize endothelial dysfunction in children with type 1 diabetes mellitus. Pediatrics 118: 242–253
Title LM, Ur E, Giddens K, McQueen MJ, Nassar BA 2006 Folic acid improves endothelial dysfunction in type 2 diabetes: an effect independent of homocysteine-lowering. Vasc Med 11: 101–109
Doshi SN, McDowell IF, Moat SJ, Payne N, Durant HJ, Lewis MJ, Goodfellow J 2002 Folic acid improves endothelial function in coronary artery disease via mechanisms largely independent of homocysteine lowering. Circulation 105: 22–26
Bostom AG, Selhub J, Jacques PF, Rosenberg IH 2001 Power shortage: clinical trials testing the “homocysteine hypothesis” against a background of folic acid-fortified cereal grain flour. Ann Intern Med 135: 133–137
Yang Q, Botto L, Erickson JD, Berry RJ, Sambell C, Johansen H, Friedman JM 2006 Improvement in stroke mortality in Canada and the United States, 1990 to 2002. Circulation 113: 1335–1343
He K, Merchant A, Rimm EB, Rosner BA, Stampfer MJ, Willett WC, Ascherio A 2004 Folate, vitamin B6, and B12 intakes in relation to risk of stroke among men. Stroke 35: 169–174
Toole JF, Malinow MR, Chambless LE, Spence JD, Pettigrew LC, Howard VJ, Sides EG, Wang CH, Stampfer M 2004 Lowering homocysteine in patients with ischemic stroke to prevent recurrent stroke, myocardial infarction, and death: the Vitamin Intervention for Stroke Prevention (VISP) randomized controlled trial. JAMA 291: 565–575
Bønaa KH, Njølstad I, Ueland PM, Schirmer H, Tverdal A, Steigen T, Wang H, Nordrehaug JE, Arnesen E, Rasmussen K, NORVIT Trial Investigators 2006 Homocysteine lowering and cardiovascular events after acute myocardial infarction. N Engl J Med 354: 1578–1588
The Heart Outcomes Prevention Evaluation (HOPE) 2 Investigators 2006 Homocysteine lowering with folic acid and B vitamins in vascular disease. N Engl J Med 354: 1567–1577
Bazzano LA, Reynolds K, Holder KN, He J 2006 Effect of folic acid supplementation on risk of cardiovascular diseases. A meta-analysis of randomized controlled trials. JAMA 296: 2720–2726
Stampfer M, Rimm E, Willett W 2006 Folate supplementation and cardiovascular disease. Lancet 367: 1237–1238
Wald DS, Morris JK, Law M, Wald NJ 2006 Folic acid, homocysteine, and cardiovascular disease: judging causality in the face of inconclusive trial evidence. BMJ 333: 1114–1117
Czeizel AE, Dobo M, Vargha P 2004 Hungarian cohort-controlled trial of periconceptional multivitamin supplementation shows a reduction in certain congenital abnormalities. Birth Defects Res A Clin Mol Teratol 70: 853–861
Botto LD, Olney RS, Erickson JD 2004 Vitamin supplements and the risk for congenital anomalies other than neural tube defects. Am J Med Genet C Semin Med Genet 125: 12–21
Goh YI, Bollano E, Einarson TR, Koren G 2006 Prenatal multivitamin supplementation and rates of congenital anomalies: a meta-analysis. J Obstet Gynaecol Can 28: 680–689
Wilcox AJ, Lie RT, Solvoll K, Taylor J, McConnaughey DR, Abyholm F, Vindenes H, Vollset SE, Drevon CA 2007 Folic acid supplements and risk of facial clefts: national population based case-control study. BMJ 334: 464
Bailey LB, Berry RJ Folic acid supplementation and the occurrence of congenital heart defects, orofacial clefts, multiple births, and miscarriage. Am J Clin Nutr 81: 1213S–1217S, 2005
Canfield MA, Collins JS, Botto LD, Williams LJ, Mai CT, Kirby RS, Pearson K, Devine O, Mulinare J, National Birth Defects Prevention Network 2005 Changes in the birth prevalence of selected birth defects after grain fortification with folic acid in the United States: findings from a multi-state population-based study. Birth Defects Res A Clin Mol Teratol 73: 679–689
Durga J, van Boxtel MP, Schouten EG, Kok FJ, Jolles J, Katan MB, Verhoef P 2007 Effect of 3-year folic acid supplementation on cognitive function in older adults in the FACIT trial: A randomised, double blind, controlled trial. Lancet 369: 208–216
Luchsinger JA, Tang M-X, Miller J, Green R, Mayeux R 2007 Relation of higher folate intake to lower risk of Alzheimer disease in the elderly. Arch Neurol 64: 86–92
D'Anci KE, Rosenberg IH 2004 Folate and brain function in the elderly. Curr Opin Clin Nutr Metab Care 7: 659–664
Kado DM, Karlamangla AS, Huang MH, Troen A, Rowe JW, Selhub J, Seeman TE 2005 Homocysteine versus the vitamins folate, B6, and B12 as predictors of cognitive function and decline in older high-functioning adults: MacArthur Studies of Successful Aging. Am J Med 118: 161–167
Ramos MI, Allen LH, Mungas DM, Jagust WJ, Haan MN, Green R, Miller JW 2005 Low folate status is associated with impaired cognitive function and dementia in the Sacramento Area Latino Study on Aging. Am J Clin Nutr 82: 1346–1352
Nurk E, Refsum H, Tell GS, Engedal K, Vollset SE, Ueland PM, Nygaard HA, Smith AD 2005 Plasma total homocysteine and memory in the elderly: the Hordaland Homocysteine Study. Ann Neurol 58: 847–857
Seshadri S, Beiser A, Selhub J, Jacques PF, Rosenberg IH, D'Agostino RB, Wilson PW, Wolf PA 2002 Plasma homocysteine as a risk factor for dementia and Alzheimer's disease. N Engl J Med 346: 476–483
Morris MC, Evans DA, Bienias JL, Tangney CC, Hebert LE, Scherr PA, Schneider JA 2005 Dietary folate and vitamin B12 intake and cognitive decline among community-dwelling older persons. Arch Neurol 62: 641–645
McMahon JA, Green TJ, Skeaff CM, Knight RG, Mann JI, Williams SM 2006 A controlled trial of homocysteine lowering and cognitive performance. N Engl J Med 354: 2764–2772
Morris MS, Jacques PF, Rosenberg IH, Selhub J 2007 Folate and vitamin B-12 status in relation to anemia, macrocytosis, and cognitive impairment in older Americans in the age of folic acid fortification. Am J Clin Nutr 85: 193–200
Institute of Medicine Food and Nutrition Board 1998 Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin and Choline. National Academy Press, Washington, DC
Savage DG, Lindenbaum J 1995 Folate-cobalamin interactions. In: Bailey LB (ed) Folate in Health and Disease. Marcel Dekker, New York, pp 237–285
Mills JL, Von Kohorn I, Conley MR, Zeller JA, Cox C, Williamson RE, Dufour DR 2003 Low vitamin B-12 concentrations in patients without anemia: the effect of folic acid fortification of grain. Am J Clin Nutr 77: 1474–1477
Kelly P, McPartlin J, Goggins M, Weir DG, Scott JM 1997 Unmetabolized folic acid in serum: acute studies in subjects consuming fortified food and supplements. Am J Clin Nutr 65: 1790–1795
Sweeney MR, McPartlin J, Weir DG, Daly S, Pentieva K, Daly L, Scott JM 2005 Evidence of unmetabolised folic acid in cord blood of newborn and serum of 4-day-old infants. Br J Nutr 94: 727–730
Shane B 1995 Folate chemistry and metabolism. In: Bailey LB (ed) Folate in Health and Disease. Marcel Dekker, New York, pp 1–22
Rimm EB, Willett WC, Hu FB, Sampson L, Colditz GA, Manson JA, Hennekens C, Stampfer MJ 1998 Folate and vitamin B6 from diet and supplements in relation to risk of coronary heart disease among women. JAMA 279: 359–364
Jacques PF, Selhub J, Bostom AG, Wilson PW, Rosenberg IH 1999 The effect of folic acid fortification on plasma folate and total homocysteine concentrations. N Engl J Med 340: 1449–1454
Huber AM, Wallins LL, DeRusso P 1988 Folate nutriture in pregnancy. J Am Diet Assoc 88: 791–795
Troen AM, Mitchell B, Sorensen B, Wener MH, Johnston A, Wood B, Selhub J, McTiernan A, Yasui Y, Oral E, Potter JD, Ulrich CM 2006 Unmetabolized folic acid in plasma is associated with reduced natural killer cell cytotoxicity among postmenopausal women. J Nutr 136: 189–194
Whiteside TL 1998 Natural killer (NK) cells. In: Delves PJ, Roitt IM (eds) Encyclopedia of Immunology, 2nd Ed. Academic Press, San Diego, pp 1809–1816
Blount BC, Mack MM, Wehr CM, MacGregor JT, Hiatt RA, Wang G, Wickramasinghe SN, Everson RB, Ames BN 1997 Folate deficiency causes uracil misincorporation into human DNA and chromosome breakage: implications for cancer and neuronal damage. Proc Natl Acad Sci USA 94: 3290–3295
Cole BF, Baron JA, Sandler RS, Haile RW, Ahnen DJ, Bresalier RS, McKeown-Eyssen G, Summers RW, Rothstein RI, Burke CA, Snover DC, Church TR, Allen JI, Robertson DJ, Beck GJ, Bond JH, Byers T, Mandel JS, Mott LA, Pearson LH, Barry EL, Rees JR, Marcon N, Saibil F, Ueland PM, Greenberg ER, Polyp Prevention Study Group 2007 Folic acid for the prevention of colorectal adenomas: a randomized clinical trial. JAMA 297: 2351–2359
Bunin GR, Kuijten RR, Buckey JD, Rorke LB, Meadows AT 1993 Relation between maternal diet and subsequent primitive neuroectodermal brain tumors in young children. N Engl J Med 329: 536–541
Preston-Martin S, Pogoda JM, Mueller BA, Lubin F, Holly EA, Filippini G, Cordier S, Peris-Bonet R, Choi W, Little J, Arslan A 1998 Prenatal vitamin supplementation and risk of childhood brain tumors. Int J Cancer Suppl 11: 17–22
Olshan AF, Smith JC, Bondy ML, Neglia JP, Pollock BH 2002 Maternal vitamin use and reduced risk of neuroblastoma. Epidemiology 13: 575–580
Goh YI, Bollano E, Einarson RE, Koren G 2007 Prenatal multivitamin supplementation and rates of pediatric cancers: a meta-analysis. Clin Pharmacol Ther 81: 685–691
French AE, Grant R, Weitzman S, Ray JG, Vermeulen MJ, Sung L, Greenberg M, Koren G 2003 Folic acid food fortification is associated with a decline in neuroblastoma. Clin Pharmacol Ther 74: 288–294
Kim YI 2004 Will mandatory folic acid fortification prevent or promote cancer?. Am J Clin Nutr 80: 1123–1128
Kim YI 2005 Nutritional epigenetics: impact of folate deficiency on DNA methylation and colon cancer susceptibility. J Nutr 135: 2703–2709
Ulrich CM, Potter JD 2007 Folate and cancer: timing is everything. JAMA 297: 2408–2409
Song J, Sohn KJ, Medline A, Ash C, Gallinger S, Kim YI 2000 Chemopreventive effects of dietary folate on intestinal polyps in Apc+/−Msh−/− mice. Cancer Res 60: 3191–3199
Song J, Medline A, Mason JB, Gallinger S, Kim YI 2000 Effects of dietary folate on intestinal tumorigenesis in the apcMin mouse. Cancer Res 60: 5434–5440
Pufulete M, Al-Ghnaniem R, Khushal A, Appleby P, Harris N, Gout S, Emery PW, Sanders TA 2005 Effect of folic acid supplementation on genomic DNA methylation in patients with colorectal adenoma. Gut 54: 648–653
Waterland RA, Jirtle RL 2003 Transposable elements: targets for early nutritional effects on epigenetic gene regulation. Mol Cell Biol 23: 5293–5300
Chabner BA, Ryan DP, Paz-Ares L, Garcia-Carbonero R, Calabresi P 2001 Antineoplastic agents. In: Hardman JG, Limbird LE, Gilman AG (eds) Goodman & Gilman's The Pharmacological Basis of Therapeutics, 10th Ed. McGraw-Hill, New York, pp 1403–1404
Strober BE, Menon K 2005 Folate supplementation during methotrexate therapy for patients with psoriasis. J Am Acad Dermatol 53: 652–659
van Ede AE, Laan RF, Rood MJ, Huizinga TW, van de Laar MA, van Denderen CJ, Westgeest TA, Romme TC, de Rooij DJ, Jacobs MJ, de Boo TM, van der Wilt GJ, Severens JL, Hartman M, Krabbe PF, Dijkmans BA, Breedveld FC, van de Putte LB 2001 Effect of folic or folinic acid supplementation on the toxicity and efficacy of methotrexate in rheumatoid arthritis: a forty-eight week, multicenter, randomized, double-blind, placebo-controlled study. Arthritis Rheum 44: 1515–1524
Barnhart KT, Gosman G, Ashby R, Sammel M 2003 The medical management of ectopic pregnancy: a meta-analysis comparing “single dose” and “multidose” regimens. Obstet Gynecol 101: 778–784
Ray JG, Langman LJ, Mamdani MM, Cole DE 2005 Absence of effect of folic acid flour fortification on anticonvalescent drug levels. Am J Med 118: 444–445
Berry RJ, Li Z, Erickson JD, Li S, Moore CA, Wang H, Mulinare J, Zhao P, Wong LY, Gindler J, Hong SX, Correa A 1999 Prevention of neural-tube defects with folic acid in China: China-US Collaborative Project for Neural Tube Defect Prevention. N Engl J Med 341: 1485–1490
Gindler J, Li Z, Berry RJ, Zheng J, Correa A, Sun X, Wong L, Cheng L, Erickson JD, Wang Y, Tong Q, Jiaxing City Collaborative Project on Neural Tube Defect Prevention 2001 Folic acid supplements during pregnancy and risk of miscarriage. Lancet 358: 796–800
Li Z, Gindler J, Wang H, Berry RJ, Li S, Correa A, Zheng JC, Erickson JD, Wang Y 2003 Folic acid supplements during early pregnancy and likelihood of multiple births: a population-based cohort study. Lancet 361: 380–384
George L, Mills JL, Johansson AL, Nordmark A, Olander B, Granath F, Cnattingius S 2002 Plasma folate levels and risk of spontaneous abortion. JAMA 288: 1867–1873
Shaw GM, Carmichael SL, Nelson V, Selvin S, Schaffer DM 2003 Food fortification with folic acid and twinning among California infants. Am J Med Genet A 119: 137–140
Waller DK, Tita AT, Annegers JF 2003 Rates of twinning before and after fortification of foods in the US with folic acid, Texas, 1996 to 1998. Paediatr Perinat Epidemiol 17: 378–383
Kucik J, Correa A 2004 Trends in twinning rates in metropolitan Atlanta before and after folic acid fortification. J Reprod Med 49: 707–712
Lawrence JM, Watkins ML, Chiu V, Erickson JD, Petitti DB 2004 Food fortification with folic acid and rate of multiple births, 1994–2000. Birth Defects Res A Clin Mol Teratol 70: 948–952
Signore C, Mills JL, Cox C, Trumble AC 2005 Effects of folic acid fortification on twin gestation rates. Obstet Gynecol 105: 757–762
Haggarty P, McCallum H, McBain H, Andrews K, Duthie S, McNeill G, Templeton A, Haites N, Campbell D, Bhattacharya S 2006 Effect of B vitamins and genetics on success of in-vitro fertilisation: prospective cohort study. Lancet 367: 1513–1519
Rothenberg SP, da Costa MP, Sequeira JM, Cracco J, Roberts JL, Weedon J, Quadros EV 2004 Autoantibodies against folate receptors in women with a pregnancy complicated by a neural-tube defect. N Engl J Med 350: 134–142
Daly LE, Kirke PN, Molloy A, Weir DG, Scott JM 1995 Folate levels and neural tube defects: Implications for prevention. JAMA 274: 1698–1702
US Department of Health and Human Services 2000 Objective 16-15, Healthy People 2010, 2nd Ed, With Understanding and Improving Health and Objectives for Improving Health ( 2 vol). Department of Health and Human Services, Washington, DC
Council on Science and Public Health; American Medical Association. Folic acid fortification of grain products. Presented as CSAPH Report 6 at the American Medical Association Annual Meeting, Chicago, June 2006. Available at: http://www.ama-assn.org/ama/pub/category/16466.html. Accessed August 12, 2007
Acknowledgements
This review was conducted under the auspices of the March of Dimes and served as a background for considering whether to petition the FDA to conduct a scientific analysis of the question posed in the title. The following individuals reviewed this article and served as liaison with their respective organizations in considering this matter: Cindy Brownstein, Spina Bifida Association; Myron Genel and Katherine Johansen, AMA; Marilyn C. Jones, ACMG; Michael Mennuti, ACOG; Claibourne I. Dungy, Ambulatory Pediatric Association; Gary L. Freed, Society for Pediatric Research; Nancy S. Green, March of Dimes; Celia I. Kaye, AAP; Edward R. B. McCabe and David K. Stevenson, American Pediatric Society. Lynn B. Bailey, Nancy S. Green, Michael Mennuti, Edward R. B. McCabe, Joe Mulinare, Godfrey P. Oakley, Jr., and Nicholas J. Wald offered constructive comments that improved the article.
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Johnston, R. Will Increasing Folic Acid in Fortified Grain Products Further Reduce Neural Tube Defects without Causing Harm?: Consideration of the Evidence. Pediatr Res 63, 2–8 (2008). https://doi.org/10.1203/PDR.0b013e31815b8ec5
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DOI: https://doi.org/10.1203/PDR.0b013e31815b8ec5
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