|Nutrition Evidence Library|
What effect has folic acid fortification policy had on serum folate, plasma and/or red blood cell folate status of US and Canadian men, women, and children?
Strong and consistent evidence demonstrates serum, plasma and red blood cell (RBC) folate concentrations have increased in the United States and Canada, following mandatory folate fortification.
Overall strength of the available supporting evidence: Strong; Moderate; Limited; Expert Opinion Only; Grade not assignable For additional information regarding how to interpret grades, click here.
Evidence Summary Overview
Of the eleven studies reviewed, seven were from the US, one from the US/Mexico border counties, and two from Canada. A third study from Canada of negative quality was not considered in forming the conclusion. Given the ecological nature of mandatory fortification, it was impossible to conduct a controlled trial during this time.
Five of the US studies (Dietrich, 2005; Dowd, 2008; Ganji, 2006; Pfeiffer, 2007; Quinlivan, 2007) used National Health and Nutrition Examination Surveys (NHANES) data for analysis; therefore, these studies are nationally representative. All of the NHANES database studies showed an increase in serum and red blood cell (RBC) folate status and a reduction in low folate concentrations. The study of Dietrich et al (2005) compared men and women aged 20 and older (non-supplement users) from NHANES III (pre-fortification) and NHANES 1999 to 2000 (post-fortification). In comparison to pre-fortification values, both serum and RBC folate levels increased significantly. Mean serum levels more than doubled (136%), and mean RBC folate levels increased 57%. The prevalence of low RBC folate decreased significantly from 39% to 3.7% between the two surveys. The NHANES studies of Ganji et al (2006), Pfeiffer et al (2007) and Quinlivan et al (2007) added additional time periods, collectively covering 1999 to 2004. In all three studies, serum and RBC folate concentrations increased significantly in the first fortification time period and then declined slightly (5% to 13% and 6% to 9%, respectively) in most age groups between the first and second or third fortification periods. The decrease in folate concentrations observed following the initial folate fortification is small in comparison to the initial increase observed and is mostly likely a result of over-fortification during the initial fortification period.
The studies of Jacques et al, 1999, and Kalmbach et al, 2008 used the Framingham database to address this question. Both studies showed increases in folate concentrations and decreases in low folate concentrations following folate fortification. In the study of Kalmbach et al, 2008, supplement users were 2.28 (95% CI: 1.7 to 3.01) times more likely to have high circulating folate concentrations than were non-supplement users.
The two Canadian studies also showed increases in folate concentrations following mandatory fortification. Bar-Oz et al, 2008 examined women of childbearing years from four general practices and two hospitals in Ontario. They demonstrated that RBC folate levels rose significantly over the years, since fortification with fewer women of childbearing years at risk for low folate concentrations. Despite these improvements, a small but significant portion of women of childbearing years are still at risk for low folate concentrations following mandatory folate fortification.
Evidence Summary Paragraphs (11)
Bar-Oz et al, 2008 (neutral quality). This trend study examined the RBCs of women of childbearing age from four general practice laboratories and two hospitals in Ontario, Canada. The results showed that RBC folic acid levels have risen significantly over the years since fortification. Also, no significant (NS) difference in the medians between 2002 (1,207nmol per L) and 2004 (928nmol per L) and between 2004 (928nmol per L) and 2005 (910nmol per L). There was a significant difference in the medians between 2005 (910nmol per L) and 2006 (972nmol per L) (P=<0.01). Overall, there was a significant decrease in the population at risk (RBC folate below either 700 or 900nmol per L) (P<0.001) from 1998 to 2002. After 2002, this trend reversed with an increase in the proportion of women with levels below 900nmol per L from 24% in 2005 to 40% in 2006. After folic acid fortification, a considerable proportion of pregnant women are still at risk of having a baby with neural tube defects (NTD).
Dietrich et al, 2005 (neutral quality) This trend study measured changes in serum and erythrocyte folate status pre- and post-fortification. The data was taken from the NHANES III and NHANES 1999 to 2000 of healthy men and women 20 years old and older and non-supplement-using. In comparison to pre-fortification values, both serum and erythrocyte folate concentrations increased significantly (P<0.0001 for all age-sex groups) post-fortification. Mean serum folate increased more than double from NHANES III to NHANES 1999 to 2000 (136%), from 11.4nmol per L to 26.9nmol per L. Mean erythrocyte folate, a marker of long-term folate status, increased 57%, (from 375nmol per L to 590nmol per L) overall. Prevalence of inadequate serum folate concentrations (less than 7nmol per L) decreased significantly from 25.77% to 0.93% (P<0.0001). Prevalence of low erythrocyte folate (less than 305nmol per L) decreased significantly from 39.07% to 3.70% (P<0.0001) between the two surveys. Mean total folate intake increased 28%, from 275ug per day to 351ug per day. In conclusion, mandatory folic acid fortification led to significant increases in both serum and erythrocyte folate concentrations; however, women of childbearing age may take supplements to reach levels associated with decreased risk of NTDs.
Dowd et al, 2008 (neutral quality), in this trend study examined the RBC of adults aged 25 years old or older. Data from NHANES survey were divided into two periods: 1) Pre-fortification [NHANES III (1991 to 1994)], and 2) Post-fortification (NHANES 1999 to 2000 and 2001 to 2002). The results showed that following fortification, the rate per 1,000 of low RBC folate status dropped from 95% CI: 528 (507, 549)nmol per L to 110 (91, 128) for the lowest income quartile, and from 374 (351, 396) to 42 (34 to 50) in the highest income quartile. The rate per 1,000 of low folate status in non-Hispanic blacks dropped from 95% CI: 647 (626, 667) to 171 (152, 190) following fortification, for Hispanics fell from 484(461, 507) to 58 (48, 67) and for non-Hispanics whites fell from 327 (310, 344) to 38 (32, 44).
Felkner et al, 2002 (neutral quality) This cross-sectional study examined the RBC of randomly selected women who delivered in a hospital or birthing center in 14 border counties from Texas-Mexico. They were controls in a population-based case-control NTD study from 1995 through 1999. Calculations showed that the median serum folate concentration increased modestly from 8.5ng per ml in 1996 to 12.4ng per ml in 1999 (46% higher). Also, the median RBC folate level increase from 272ng per ml in 1996 to 393ng per ml in 1999 (44% higher). The median RBC folate concentration in women, who were not prenatal vitamin users was 254ng per ml in 1996 and 378ng per ml in 1999 (49% increase). In conclusion, serum and RBC folate levels appear to have risen in this postpartum Texas-Mexico border population from 1996 through 1999. (Test for statistical difference is not mentioned.)
Ganji et al, 2006 (neutral quality) This trend study examined the serum and RBC folate of three NHANES survey periods: 1) NHANES III (1988 to 1994); 2) NHANES 1999 to 2000; and 3) NHANES 2001 to 2002. Serum and RBC folate concentrations were significantly higher and the prevalence of low serum and RBC folate concentrations were significantly lower in period 2 and 3 than in period 1, in all demographic groups of the US. Overall, mean serum folate concentrations were higher in period 2 (149.6%) and in period 3 (129.8%) than in period 1. From period 2 to 3, serum folate concentration significantly decline in men (7.3%, P=0.0012), in women (8.5%, P=0.0028), in non-Hispanic whites (NHW) (9.7%, P=0.0037), in those 18 years old (7.3%, P=0.0081), in those 31 to 50 years old (7.6%, P=0.0021), in those 51 to 70 years old (10.8%, P=0.0146) and in those with poverty income ratio (PIR) 1.0 (12.5%, P=0.0063) and $4.0 (9.9%, P=0.0068). When the data were adjusted for sex, age and race-ethnicity, there was a reduction of 10.4% in serum folate concentrations from period 2 to 3 (P<0.0002). Overall, mean RBC folate concentrations were 58.2% higher in period 2 and 56.5% higher in period 3 than in period 1. When the data were adjusted for sex, age and race-ethnicity, similar trends were present for RBC folate.
Jacques et al, 1999 (positive quality) This trend study assessed the effect of folic acid fortification on folate status. Plasma folate and total homocysteine concentrations were measured in a cohort of participants from the fifth and sixth examination Framingham study. The data were divided in two groups: 1) Baseline (fifth examination before fortification policy); 2) Follow-up (sixth examination after fortification policy); and 3) Control group (sixth examination before fortification policy began). Among the subjects who did not use vitamin supplements, the mean folate concentrations increased from the baseline to the follow-up visit, from 4.6 to 10.0ng per ml (11 to 23nmol per L) (P<0.001), increasing by 117% after fortification. The prevalence of low folate concentrations decreased from 22.0% to 1.7% (P< 0.001), decreasing by 92% [less than 3ng per ml (7nmol per L)]. In the control group, there were no statistically significant changes in concentrations of folate or homocysteine. The fortification of enriched grain products with folic acid was associated with a substantial improvement in folate status in a population of middle-aged and older adults.
Kalmbach et al, 2008 (positive quality) This cross-sectional study assessed the effect of folic acid fortification implementation on total plasma folate, circulation concentration of folic acid and 5-methyltetrahydrofolate (5MeTHF) in the Framingham Offspring Cohort. Among nonsupplement users, median circulating concentrations of folic acid increased after fortification (from 0.25 to 0.50nmol per L, P<0.001). The prevalence of detectable circulating folic acid was 55% before and 74.7% after fortification (P<0.001). The prevalence of high circulating folic acid was 9.4% before and 19.1% after fortification (P=0.002). Plasma folate concentrations were 91% higher after fortification (P<0.001) and 5MeTHF concentrations were 92% higher after fortification (P<0.001). Among B-vitamin supplements users, median circulating concentrations of folic acid increased after fortification from 0.54 to 0.68 (P=0.001). The prevalence of detectable circulating folic acid was 72.5% before fortification and 80.7% after fortification (P=0.13). The prevalence of high circulating folic acid increased from 15.9% to 24.3% after fortification (P=0.02). Total plasma folate concentration was 29.9% higher after fortification (P<0.001) and 5MeTHF concentrations were 28.7% higher (P<0.001) after fortification. A trend was observed for an increased prevalence of high circulating folic acid as the total folate intake increased (P<0.001). After adjusted for age, sex, vitamin intakes and total energy intake, folic acid intake, total folate intake, use of B-vitamin supplements and total plasma folate were the only significant determinants identified. Supplements users were 2.28 (95% CI: 1.7, 3.01) times more likely to have high circulating folic acid than were non-supplement users.
Pfeiffer et al, 2007 (positive quality) This trend study evaluated data from participants in the pre-fortification NHANES III (1988 to 1994), and participants in three post-fortification NHANES periods (covering 1999 to 2004). Measurements were comparing for serum folate for 1988 to 1994 and 1999 to 2004, vitamin B12 for 1991 to 1994 and 1999 to 2004, and RBC folate for 1988 to 1994 and 1999 to 2004. Serum and RBC folate concentrations increased substantially (by 119% to 161 % and 44% to 64%, respectively) in each age group in the first post-fortification survey period and then declined slightly (by 5% to 13% and 6% to 9%, respectively) in most age groups between the first and third post-fortification survey periods. Serum vitamin B12 concentrations did not change appreciably. Prevalence estimates of low serum and RBC folate concentration declined in women of childbearing age from before to after fortification (from 31% to less than 1% and from 38% to 5%, respectively) but remained unchanged thereafter. Prevalence estimates of high serum folate concentrations increased in children and older persons from before to after fortification (from 5% to 42% and from 7% to 38%, respectively) but decreased later after fortification. The authors concluded that decrease in folate concentrations observed longer after fortification is small compared with the increased soon after the introduction of fortification.
Quinlivan et al, 2007 (neutral quality), in this trend study used NHANES data to quantify changes in folate intake after folic acid fortification and estimated the effect on NTD occurrence. Three waves of NHANES data were divided in two periods: Pre-fortification (1988 to 1994) and post-fortification (1999 to 2000 and 2001 to 2004). Red blood cell and serum folate concentrations increased between 1988 to 1994 and 1999 to 2000, and then they decreased each year from 1999 to 2000 to 2003 to 2004. Between 1988 to 1994 and 1999 to 2000, the percentage increase in serum and RBC folate concentration was smallest in the women with the highest folate status. Median folate consumption of the study population increased by 529µg dietary folate equivalent (DFE) per day between before fortification and after fortification; then decreased by 135µg DFE per day between 1999 to 2000 and 2003 to 2004. The overall decrease in folate consumption was primarily due to changes in subjects with the highest folate status. Total folate consumption increased in the year after mandatory fortification. However, by 2003 to 2004, total folate consumed by subjects in the 90th percentile had decreased to 1,249µg DFE per day.
Ray et al, 2002 (neutral quality), This cross-sectional study examined the changes in rates of serum folate, RBC folate and vitamin B12 insufficiency among Canadian adults after the mandatory folic acid food fortification program was implemented. Data from 8,884 individuals who underwent evaluation were evaluated, organized on the following periods: 1) Period 1 (April 1, 1997 to July 31, 1998); 2) Period 2 (August 1, 1998 to January 30, 1999); and 3) Period 3 (February 1, 1999 to March 31, 2000). The prevalence of serum folate insufficiency (less than 3.4nmol per L) fell from 0.52% in period 1 to 0.22% in period 3 [prevalence ratio (RR) 0.41%, 95% CI: 0.18, 0.93]. The prevalence of RBC folate insufficiency (less than 215nmol per L) declined from 1.78% during period 1 to 0.41%in period 3 (RR 0.23, 95% CI: 0.14 to 0.40). No significant difference was observed between periods in the prevalence of B12 insufficiency below 120nmol per L (3.93% vs. 3.11%, respectively; RR 0.79, 95% CI: 0.62, 1.01).
Shuaibi et al, 2008 (negative quality) In this cross-sectional study of 95 women, the University of Manitoba assessed descriptive statistics for serum and RBC folate and total homocysteine. Also, assessed total folate intake (from natural food folate, folic acid added to food and folic acid supplements) and used T-tests to assess differences in folate intake between supplement users and non-users (P<0.05). The intake of natural food folate, expressed as micrograms, was 1.6 times more than the total folic acid from food and supplements intake expressed as micrograms, and almost the same when expressed as Dietary Folate Equivalents (DFEs). The total intakes for folate were significantly higher for supplement users compared to supplement non-users. The mean±SD, median and the range (10th and 90th percentile) for serum folate were, respectively, 14.6±3.5, 14.1 and 10.0 to 19.3ng per ml (33.0±7.9, 32.0 and 22.6 to 43.8nmol per L); for RBC folate, the values were 312.0±137.2, 286.8 and 180.5 to 462.9ng per ml (707±311, 650 and 409 to 1,049nmol per L), respectively. Also, no women were folate deficient and 14% reached RBC folate higher than 400ug per day. Finally, intakes of folic acid from fortified foods are within the level originally predicted for the fortification efforts but only 17% of participants met the special recommendation for women of childbearing age (400ug folic acid daily from supplements, fortified foods or both in addition to consuming food folate from diet). This data suggest that women of childbearing age are increasing RBC folate status but it may not be sufficient to achieve values associated with reduction of NTD risk.
View table in new window
Research Design and Implementation Rating Summary
For a summary of the Research Design and Implementation Rating results, click here.
Bar-Oz B, Koren G, Nguyen P, Kapur BM. Folate fortification and supplementation: Are we there yet? Reprod Toxicol. 2008 Aug; 25 (4): 408-412.
Dietrich M, Brown CJP, Block G. The effect of folate fortification of cereal-grain products on blood folate status, dietary folate intake and dietary folate sources among adult non-supplement users in the United States. Journal of the American College of Nutrition 2005; 24 (4): 266-274.
Dowd JB, Aiello AE. Did national folic acid fortification reduce socioeconomic and racial disparities in folate status in the US? Int J Epidemiol. 2008; 37 (5): 1,059-1,066.
Felkner M, Suarez L, Hendricks K, Gunter EW. Blood folate levels on the Texas-Mexico border. Tex Med. 2002; 98 (11): 58-60.
Ganji V, Kafai MR. Trends in serum folate, RBC folate, and circulating total homocysteine concentrations in the United States: Analysis of data from National Health and Nutrition Examination Surveys, 1988-1994, 1999-2000, and 2001-2002. J Nutr. 2006 Jan; 136 (1): 153-158.
Jacques PF, Selhub J, Bostom AG, Wilson PW, Rosenberg IH. The effect of folic acid fortification on plasma folate and total homocysteine concentrations. N Engl J Med. 1999; 340: 1,449-1,454.
Kalmbach RD, Choumenkovitch SF, Troen AM, D'Agostino R, Jacques PF, Selhub J. Circulating folic acid in plasma: Relation to folic acid fortification. Am J Clin Nutr. 2008; 88 (3): 763-768.
Pfeiffer CM, Johnson CL, Jain RB, Yetley EA, Picciano MF, Rader JI, Fisher KD, Mulinare J, Osterloh JD. Trends in blood folate and vitamin B-12 concentrations in the United States, 1988-2004. Am J Clin Nutr. 2007; 86 (3): 718-727.
Quinlivan EP, Gregory JF 3rd. Re-assessing folic acid consumption patterns in the United States (1999 to 2004): Potential effect on neural tube defects and overexposure to folate. Am J Clin Nutr. 2007 Dec; 86 (6): 1,773-1,779.
Ray JG, Vermeulen MJ, Boss SC, Cole DEC. Declining rate of folate insufficiency among adults following increased folic acid food fortification in Canada. Can J Public Health. 2002 Jul-Aug; 93 (4): 249-253.
Shuaibi AM, House JD, Sevenhuysen GP. Folate status of young Canadian women after folic acid fortification of grain products. J Am Diet Assoc. 2008 Dec; 108 (12): 2,090-2,094.