Implementation Of Folic Acid Fortification Research Articles

Global heterogeneity in folic acid fortification policies and implications for prevention of neural tube defects and stroke: a systematic review

Folic acid (pteroylmonoglutamic acid) supplements are highly effective for prevention of neural tube defects (NTD) prompting implementation of mandatory or voluntary folic acid fortification for prevention of NTDs. We used plasma folate levels in population studies by country and year to compare effects of folic acid fortification types (mandatory or voluntary folic acid fortification policies) on plasma folate levels, NTD prevalence and stroke mortality rates. We conducted systematic reviews of (i) implementation of folic acid fortification in 193 countries that were member states of the World Health Organization by country and year, and (ii) estimated population mean plasma folate levels by year and type of folic acid fortification. We identified relevant English language reports published between Jan 1, 1990 and July 31, 2023 using Google Scholar, Medline, Embase and Global Health. Eligibility criteria were observational or interventional studies with >1000 participants. Studies of pregnant women or children <15 years were excluded. Using an ecological study design, we examined the associations of folic acid fortification types with NTD prevalence (n=108 studies) and stroke mortality rates (n=3 countries). Among 193 countries examined up to 31 July 2023, 69 implemented mandatory folic acid fortification, 47 had voluntary fortification, but 77 had no fortification (accounting for 32%, 53% and 15% of worldwide population, respectively). Mean plasma folate levels were 36, 21 and 17nmol/L in populations with mandatory, voluntary and no fortification, respectively (and proportions with mean folate levels >25nmol/L were 100%, 15% and 7%, respectively). Among 75 countries with NTD prevalence, mean (95% CI) prevalence per 10,000 population were 4.19 (4.11-4.28), 7.61 (7.47-7.75) and 9.66 (9.52-9.81) with mandatory, voluntary and no folic acid fortification, respectively. However, age-standardised trends in stroke mortality rates were unaltered by the introduction of folic acid fortification. There is substantial heterogeneity in folic acid fortification policies worldwide where folic acid fortification are associated with 50-100% higher population mean plasma folate levels and 25-50% lower NTD prevalence compared with no fortification. Many thousand NTD pregnancies could be prevented yearly if all countries implemented mandatory folic acid fortification. Further trials of folic acid for stroke prevention are required in countries without effective folic acid fortification policies. Medical Research Council (UK) and British Heart Foundation.

Population-wide folic acid fortification and preterm birth: testing the folate depletion hypothesis.

We assess whether population-wide folic acid fortification policies were followed by a reduction of preterm and early-term birth rates in Québec among women with short and optimal interpregnancy intervals. We extracted birth certificate data for 1.3 million births between 1981 and 2010 to compute age-adjusted preterm and early-term birth rates stratified by short and optimal interpregnancy intervals. We used Joinpoint regression to detect changes in the preterm and early term birth rates and assess whether these changes coincide with the implementation of population-wide folic acid fortification. A change in the preterm birth rate occurred in 2000 among women with short (95% confidence interval [CI] = 1994, 2005) and optimal (95% CI = 1995, 2008) interpregnancy intervals. Changes in early term birth rates did not coincide with the implementation of folic acid fortification. Our results do not indicate a link between folic acid fortification and early term birth but suggest an improvement in preterm birth rates after implementation of a nationwide folic acid fortification program.

Serum folate concentrations and cancer risk in older U.S. adults in the post‐folic acid fortification period (384.5)

Studies have reported an increase in total serum folate since the implementation of folic acid fortification on January 1, 1998. However, the literature published during the post‐folic acid fortification period is controversial with regards to the safety and potential risk for cancer in non‐target population. The association between serum folate and cancer in older US adults was investigated. Data from NHANES 1999‐2008 were used to form the study population. Among 7981 subjects who were aged &gt;60y and had a measured serum folate from 1999‐2008, 1459 reported having cancer. Among 4007 women who were aged 60+ and had serum folate measured between 1999 and 2008, 288 reported a history of breast cancer. The study population was categorized into four equal‐size groups using the serum folate quartiles as cutoff values and odds ratio of having cancer was calculated between these four groups. Those over the age of 60y with the highest concentration (fourth quartile) of serum folate were 1.6 times more likely to have cancer than participants with lowest serum folate (first quartile) (P&lt;0.001). Women over the age of 60y with the highest concentration of serum folate (fourth quartile) were 1.5 times more likely to have breast cancer compared to women with lowest serum folate (first quartile) (P=0.004). The presence of high total serum folate was related to an increased prevalence of cancer. Because of cross‐sectional nature of the data, the cause and effect relationship should not be inferred. Further research is warranted to investigate the cause and effect relationship between serum folate and cancer.Grant Funding Source: Department of Nutrition, Georgia State University

Serum Folate but Not Vitamin B-12 Concentrations Are Positively Associated with Cognitive Test Scores in Children Aged 6–16 Years

Folate and vitamin B-12 are important for nervous system functioning at all ages, with important roles in functions such as neurotransmitter synthesis. Although studies suggest a relation between folate and vitamin B-12 and cognitive function in the elderly population, there is relatively less evidence regarding these vitamins and children's cognitive function. The purpose of the study was to examine the associations of serum folate and vitamin B-12 with cognitive performance in children 6–16 y old in the NHANES III, conducted from 1988 to 1994, prior to the implementation of folic acid fortification. A cross-sectional analysis was conducted using data on 5365 children 6–16 y old from NHANES III. Serum folate and vitamin B-12 concentrations were measured, along with performance, on the Wide Range Achievement Test-Revised and the Wechsler Intelligence Scale for Children-Revised. Associations of B vitamins with cognitive performance were assessed using linear regression models adjusted for various covariates. Higher serum concentrations of folate were associated with higher reading and block design scores after adjusting for various covariates. For example, compared with the lowest quartile of folate, children in the highest quartile scored 3.28 points or 0.19 SD units higher on the reading test (P < 0.05). Vitamin B-12 was not associated with any of the test scores. In the largest study to date, higher folate concentrations were associated with better reading and block design scores. These associations appear to be biologically plausible and merit further study.

Folic acid fortification prevents neural tube defects and may also reduce cancer risks

The prevalence of neural tube defect (NTD)-affected pregnancies ranges between 0.4 and 2/1000 pregnancies in EU. NTDs result in severe malformations and sometimes miscarriages. Children born with NTD suffer for the rest of their life of disability and chronic healthcare issues, and many women therefore choose termination of pregnancy if NTD is diagnosed prenatally. Women planning for pregnancy are recommended to eat 400 μg folic acid/d, whereas average figures across Europe indicate intakes of ∼250 μg/d for women of fertile age, a gap that could be bridged by implementation of folic acid fortification. The results of mandatory folic acid fortifications introduced in USA and Canada are a decrease between 25 and 45% of NTD pregnancies. Evidence-based NTD prophylaxis is now practised in more than 60 countries worldwide. EU countries worry over possible cancer risks, but ignore a wealth of studies reporting decreasing cancer risks with folate intakes at recommended levels. Currently, there are indications of a U-shaped relationship, that is, higher cancer risks at low folate intakes (<150 μg/day) and highly elevated folate intakes (>1 mg/day), respectively. However neither the global World Cancer Research review nor EU's European Food Safety Authority report present data on increased cancer risk at physiological folate intake levels. Therefore, EU should act to implement folic acid fortification as NTD prophylaxis as soon as possible.

Monitoring folate status in population‐based surveys

Folate status assessments depend primarily on the measurement of biomarkers such as serum and red blood cell folate. Lessons learned from a large national monitoring system such as the National Health and Nutrition Examination Survey and a public health intervention such as the implementation of folic acid fortification in the United States have provided useful insights into the challenges of assessing folate status and possible solutions for addressing these challenges. © 2011 International Union of Biochemistry and Molecular Biology, Inc. 2011.

NTD Prevalences in Central California Before and After Folic Acid Fortification

Soon after the implementation of folic acid fortification in cereal grain products in 1998, several reports appeared in the medical literature showing a reduction in the prevalence of neural tube defects (NTDs). However, a number of investigators observed an ongoing background trend for decreased prevalence of NTDs that began before the implementation of fortification. It is therefore possible that the apparent reduction produced by folic acid fortification actually results from continuation of that trend. Previous studies obtained prevalence ratios consistent with a beneficial effect of fortification through use of a summary of prevalence before and after fortification. Their data, however, do not include an analysis of the magnitude and direction of the change in prevalence over time. This population-based study was designed to determine whether the trend for decline in the prevalence of NTDs observed before fortification (1989-1996) continued after fortification (1998-2003) in 8 central California counties. The study population included all live births, and stillbirths delivered in 8 central California counties from 1989 to 2003. The authors recorded the total number of NTD cases each year. Over the entire study period (1989-2003), 690 of the 886,985 total deliveries were NTD cases. This corresponds to an average prevalence of 77.8 cases per 100,000 deliveries. The authors compared the slopes of two regression lines, pre and postfortification, to provide an estimate of the annual change in NTD prevalence, and to compare the pre and postfortification changes in NTD prevalences over time. Analysis of the slope data for all NTDs combined showed that before fortification NTD prevalences were decreasing by 7.5 (slope: 27.5; 95% confidence interval [CI]: 212.4, 22.5) cases per 100,000 deliveries per year. After fortification, NTD prevalences were no longer decreasing. The postfortification slope exceeded the prefortification slope by 12.6 (95% CI: 2.6, 22.6) cases per 100,000 deliveries per year. These findings do not appear to result from low intake of folic acid during the postfortification period or differences in maternal race, ethnicity, or obesity. The authors conclude from these findings that the observed decline in NTD prevalence before fortification did not continue after fortification in selected central California counties. The data provide no evidence that fortification with folic acid reduced the prevalence of NTDs in this selected population.

Circulating folic acid in plasma: relation to folic acid fortification

BackgroundThe implementation of folic acid fortification in the United States has resulted in unprecedented amounts of this synthetic form of folate in the American diet. Folic acid in circulation may be a useful measure of physiologic exposure to synthetic folic acid, and there is a potential for elevated concentrations after fortification and the possibility of adverse effects. ObjectiveWe assessed the effect of folic acid fortification on circulating concentrations of folic acid and 5-methyltetrahydrofolate in the Framingham Offspring Cohort. DesignThis is a cross-sectional study that used plasma samples from fasting subjects before and after fortification. Samples were measured for folate distribution with the use of an affinity-HPLC method with electrochemical detection. ResultsAmong nonsupplement users, the median concentration of folic acid in plasma increased from 0.25 to 0.50 nmol/L (P < 0.001) after fortification, and among supplement users the median increased from 0.54 to 0.68 nmol/L (P = 0.001). Among nonsupplement users, the prevalence of high circulating folic acid (≥85th percentile) increased from 9.4% to 19.1% (P = 0.002) after fortification. Among supplement users, the prevalence of high circulating folic acid increased from 15.9% to 24.3% (P = 0.02). Folic acid intake and total plasma folate were positively and significantly related to high circulating folic acid after adjustment for potential confounding factors (P for trend < 0.001). ConclusionsFolic acid fortification has resulted in increased exposure to circulating folic acid. The biochemical and physiologic consequences of this are unknown, but these findings highlight the need to understand the effects of chronic exposure to circulating folic acid.

NTD prevalences in central California before and after folic acid fortification

In many regions, NTD prevalences were already declining prior to folic acid fortification. This study examined whether the declining prefortification (1989-1996) NTD prevalences continued into the postfortification period (1998-2003) in selected California counties. This population-based study used vital statistics data and birth defects registry data that were actively ascertained from medical records. The study population included all live births and stillbirths delivered in central California counties from 1989 to 2003. Cases included deliveries with NTDs during the same time period. For all NTDs combined, the slopes indicated that NTD prevalence was decreasing by 7.5 (slope: -7.5; 95% CI: -12.4, -2.5) cases per 100,000 deliveries per year before fortification, whereas NTD prevalence was no longer decreasing after fortification. Comparison of the difference in the two slopes indicated that the postfortification slope exceeded the prefortification slope by 12.6 (95% CI: 2.6, 22.6) cases per 100,000 deliveries per year. Annual NTD prevalences in central California did not continue to decrease after implementation of folic acid fortification.

Folate and vitamin B12: friendly or enemy nutrients for the elderly

In the UK vitamin B12 deficiency occurs in approximately 20% of adults aged >65 years. This incidence is significantly higher than that among the general population. The reported incidence invariably depends on the criteria of deficiency used, and in fact estimates rise to 24% and 46% among free-living and institutionalised elderly respectively when methylmalonic acid is used as a marker of vitamin B12 status. The incidence of, and the criteria for diagnosis of, deficiency have drawn much attention recently in the wake of the implementation of folic acid fortification of flour in the USA. This fortification strategy has proved to be extremely successful in increasing folic acid intakes pre-conceptually and thereby reducing the incidence of neural-tube defects among babies born in the USA since 1998. However, in successfully delivering additional folic acid to pregnant women fortification also increases the consumption of folic acid of everyone who consumes products containing flour, including the elderly. It is argued that consuming additional folic acid (as 'synthetic' pteroylglutamic acid) from fortified foods increases the risk of 'masking' megaloblastic anaemia caused by vitamin B12 deficiency. Thus, a number of issues arise for discussion. Are clinicians forced to rely on megaloblastic anaemia as the only sign of possible vitamin B12 deficiency? Is serum vitamin B12 alone adequate to confirm vitamin B12 deficiency or should other diagnostic markers be used routinely in clinical practice? Is the level of intake of folic acid among the elderly (post-fortification) likely to be so high as to cure or 'mask' the anaemia associated with vitamin B12 deficiency?

A comprehensive evaluation of food fortification with folic acid for the primary prevention of neural tube defects.

BackgroundPericonceptional use of vitamin supplements containing folic acid reduces the risk of a neural tube defect (NTD). In November 1998, food fortification with folic acid was mandated in Canada, as a public health strategy to increase the folic acid intake of all women of childbearing age. We undertook a comprehensive population based study in Newfoundland to assess the benefits and possible adverse effects of this intervention.MethodsThis study was carried out in women aged 19–44 years and in seniors from November 1997 to March 1998, and from November 2000 to March 2001. The evaluation was comprised of four components: I) Determination of rates of NTDs; II) Dietary assessment; III) Blood analysis; IV) Assessment of knowledge and use of folic acid supplements.ResultsThe annual rates of NTDs in Newfoundland varied greatly between 1976 and 1997, with a mean rate of 3.40 per 1,000 births. There was no significant change in the average rates between 1991–93 and 1994–97 (relative risk [RR] 1.01, 95% confidence interval [CI] 0.76–1.34). The rates of NTDs fell by 78% (95% CI 65%–86%) after the implementation of folic acid fortification, from an average of 4.36 per 1,000 births during 1991–1997 to 0.96 per 1,000 births during 1998–2001 (RR 0.22, 95% CI 0.14–0.35). The average dietary intake of folic acid due to fortification was 70 μg/day in women aged 19–44 years and 74 μg/day in seniors. There were significant increases in serum and RBC folate levels for women and seniors after mandatory fortification. Among seniors, there were no significant changes in indices typical of vitamin B12 deficiencies, and no evidence of improved folate status masking haematological manifestations of vitamin B12 deficiency. The proportion of women aged 19–44 years taking a vitamin supplement containing folic acid increased from 17% to 28%.ConclusionsBased on these findings, mandatory food fortification in Canada should continue at the current levels. Public education regarding folic acid supplement use by women of childbearing age should also continue.

Effect of implementation of folic acid fortification of food on homocysteine concentrations in subjects with coronary artery disease

In summary, because folic acid may reduce HCY plasma levels, a new risk factor for CAD, we tested whether an FDA mandate for folic acid fortification of foods would affect plasma HCY among 2,755 subjects studied angiographically over 4 years and at high risk of incident coronary events. Plasma HCY declined by 2 μmol/L, and the percentage of patients with high-risk HCY decreased by 1/3 in temporal association with implementation of the FDA rule.

Determinants of plasma total homocysteine concentration in the Framingham Offspring cohort

Established determinants of fasting total homocysteine (tHcy) concentration include folate and vitamin B-12 status, serum creatinine concentration, and renal function. Our objective was to examine the relation between known and suspected determinants of fasting plasma tHcy in a population-based cohort. We examined the relations between fasting plasma tHcy concentrations and nutritional and other health factors in 1960 men and women, aged 28-82 y, from the fifth examination cycle of the Framingham Offspring Study between 1991 and 1994, before the implementation of folic acid fortification. Geometric mean tHcy was 11% higher in men than in women and 23% higher in persons aged > or = 65 y than in persons aged < 45 y (P < 0.001). tHcy was associated with plasma folate, vitamin B-12, and pyridoxal phosphate (P for trend < 0.001). Dietary folate, vitamin B-6, and riboflavin were associated with tHcy among non-supplement users (P for trend < 0.01). The tHcy concentrations of persons who used vitamin B supplements were 18% lower than those of persons who did not (P < 0.001). tHcy was positively associated with alcohol intake (P for trend = 0.004), caffeine intake (P for trend < 0.001), serum creatinine (P for trend < 0.001), number of cigarettes smoked (P for trend < 0.001), and antihypertensive medication use (P < 0.001). Our study confirmed, in a population-based setting, the importance of the known determinants of fasting tHcy and suggested that other dietary and lifestyle factors, including vitamin B-6, riboflavin, alcohol, and caffeine intakes as well as smoking and hypertension, influence circulating tHcy concentrations.

The study of neural tube defects after the Human Genome Project and folic acid fortification of foods.

The implementation of folic acid fortification will eliminate a proportion of neural tube defects (NTD). As a result, the etiologic and clinical profiles of the developmental disorder may both change. In the assessment of NTD as it evolves, the bioinformatics structure and content of the Human Genome Project will find vital application. One important development will be an enhanced understanding of the role of folic acid in global regulation of gene expression through epigenetic processes. In addition, bioinformatics will facilitate coordination of research in the basic sciences with clinical investigations to better define remaining etiologic factors.