Folate during reproduction: the Canadian experience with folic acid fortification

Four Years After Enhanced Folic Acid Fortification of the Canadian Food Supply — How Are We Doing?

Background Neural tube defects (NTDs) remain an important, preventable cause of mortality and morbidity. High-income countries have reported large reductions in NTDs associated with folic acid supplementation or fortification. The burden of NTDs in low-income countries and the effectiveness of folic acid fortification/supplementation are unclear.Objective To review the evidence for, and estimate the effect of, folic acid fortification/supplementation on neonatal mortality due to NTDs, especially in low-income countries.Methods We conducted systematic reviews, abstracted data meeting inclusion criteria and evaluated evidence quality using adapted Grading of Recommendations, Assessment, Development and Evaluation (GRADE) methodology. Where appropriate, meta-analyses were performed.Results Meta-analysis of three randomized controlled trials (RCTs) of folic acid supplementation for women with a previous pregnancy with NTD indicates a 70% [95% confidence interval (CI): 35–86] reduction in recurrence (secondary prevention). For NTD primary prevention through folic acid supplementation, combining one RCT with three cohort studies which adjusted for confounding, suggested a reduction of 62% (95% CI: 49–71). A meta-analysis of eight population-based observational studies examining folic acid food fortification gave an estimated reduction in NTD incidence of 46% (95% CI: 37–54). In low-income countries an estimated 29% of neonatal deaths related to visible congenital abnormalities are attributed to NTD. Assuming that fortification reduces the incidence of NTDs, but does not alter severity or case-fatality rates, we estimate that folic acid fortification could prevent 13% of neonatal deaths currently attributed to congenital abnormalities in low-income countries.Discussion Scale-up of periconceptional supplementation programmes is challenging. Our final effect estimate was therefore based on folic acid fortification data. If folic acid food fortification achieved 100% population coverage the number of NTDs in low-income countries could be approximately halved.Conclusion The evidence supports both folic acid supplementation and fortification as effective in reducing neonatal mortality from NTDs.

BackgroundIn 1998, mandatory folic acid fortification of white flour and select cereal grain products was implemented in Canada with the intention to increase dietary folate intakes of reproducing women. Folic acid fortification has produced a dramatic increase in blood folate concentrations among reproductive age women, and a reduction in neural tube defect (NTD)-affected pregnancies. In response to improved blood folate concentrations, many health care professionals are asking whether a folic acid supplement is necessary for NTD prevention among women with high blood folate values, and how reliably high RBC folate concentrations predict folate intakes shown in randomized controlled trials to be protective against NTDs. The objective of this study was to determine how predictive blood folate concentrations and folate intakes are of each other in a sample of well-educated lactating Canadian women exposed to high levels of synthetic folate.MethodsThe relationship between blood folate concentrations and dietary folate intakes, determined by weighed food records, were assessed in a sample of predominantly university-educated lactating women (32 ± 4 yr) at 4-(n = 53) and 16-wk postpartum (n = 55).ResultsMedian blood folate concentrations of all participants were well above plasma and RBC folate cut-off levels indicative of deficiency (6.7 and 317 nmol/L, respectively) and all, except for 2 subjects, were above the cut-off for NTD-risk reduction (>906 nmol/L). Only modest associations existed between total folate intakes and plasma (r = 0.46, P < 0.001) and RBC (r = 0.36, P < 0.01) folate concentrations at 16-wk postpartum. Plasma and RBC folate values at 16-wk postpartum correctly identified the quartile of folate intake of only 26 of 55 (47%) and 18 of 55 (33%) of subjects, respectively. The mean RBC folate concentration of women consuming 151–410 μg/d of synthetic folate (2nd quartile of intake) did not differ from that of women consuming >410 μg/d (3rd and 4th quartile).ConclusionFolate intakes, estimated by food composition tables, and blood folate concentrations are not predictive of each other in Canadian lactating women exposed to high levels of folate. Synthetic intakes > 151–410 μg/d in these women produced little additional benefit in terms of maximizing RBC content. More studies are needed to examine the relationship between blood folate concentration and NTD risk. Until data from such studies are available, women planning a pregnancy should continue to consume a daily folic acid supplement of 400 μg.

Focused Revision: Policy statement on folic acid and neural tube defects

To review the impact of folic acid fortification of flour on the prevalence of neural tube defects (NTD). Systematic review of the literature on MEDLINE via PubMed, Scopus, OvidSP and LILACS (Latin American and Caribbean Health Sciences Literature) reporting the impact of folic acid fortification of flour on the prevalence of NTD in 2000-2011. Focusing on Santiago of Chile's birth defects registry (1999-2009) and the monitoring of flour fortification, we analysed the prevalence (NTD cases/10 000 births) pre and post flour fortification and the percentile distribution of folic acid content in flour (2005-2009). We explored the potential association between median folic acid in flour (mg/kg) and the prevalence of NTD. Chile, Argentina, Brazil, Canada, Costa Rica, Iran, Jordan, South Africa and the USA. Live births and stillbirths. Twenty-seven studies that met inclusion criteria were evaluated. Costa Rica showed a significant reduction in NTD (∼60 %). Prevalence in Chile decreased from 18·6 to 7·3/10 000 births from 1999 to 2007 and showed a slight increase to 8·5 in 2008-2009, possibly due to changes in fortification limits. When we related the prevalence of NTD with levels of flour fortification, the lowest prevalence was observed at a folic acid level of 1·5 mg/kg. Fortification of flour with folic acid has had a major impact on NTD in all countries where this has been reported. Chile showed a 55 % reduction in NTD prevalence between 1999 and 2009. There is a need to constantly monitor the levels of flour fortification to maximize benefits and prevent the potential risk of folic acid excess, moreover to be vigilant for any new adverse effects associated with excess.

Should Europe fortify a staple food with folic acid?

Some, but not complete, reassurance on the safety of folic acid fortification

Folic acid is an essential water soluble B vitamin which has been used for decades in the prevention of folate deficiency anemia of pregnancy. In 1991, folic acid taken prior to the start of pregnancy was shown unequivocally to prevent spina bifida and anencephaly—two of the most serious and common birth (neural tube) defects. Soon governments recommended that women of reproductive age consume folic acid daily to prevent these birth defects. Because compliance was low and since more than half of pregnancies are unplanned, the United States Food and Drug Administration mandated in 1998 that all enriched flour be fortified with folic acid at a concentration estimated to give the average woman an intake of 100 micrograms of folic acid a day. Canada and Chile followed with similar requirements for folic acid fortification of wheat flour. Now there is mandatory fortification in more than 50 countries globally. Where fortification has been implemented and studied, it has led to dramatic increases in serum folate concentrations, reduction in neural tube defects, folate deficiency anemia, as well as the reduction in homocysteine concentrations and stroke mortality with no known risk. Australia implemented mandatory folic acid fortification in 2009. To date, no country in Europe has implemented mandatory folic acid fortification of flour, although it has been recommended by the UK Food Safety Authority. This review discusses the vital importance of mandatory flour fortification with folic acid and vitamin B12, for public health food security and as a challenge to the New Public Health in Europe and globally.

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Neural tube defects (NTDs), such as spinal cord and brain defects, are due to abnormal embryonic development of the neural tube and associated with increased fetal and infant mortality, morbidity, lifelong disability, and high economic costs. Globally, more than 260,000 pregnancies are estimated to be affected by NTDs, and 75% of the NTD live births result in under-5 deaths.1 Majority of NTDs are folic acid-sensitive; with much of the NTD burden preventable through consumption of folic acid before and during early pregnancy (periconception). An association between low folate status of women of reproductive age (WRA) and risk of NTD-affected pregnancy was first proposed in 1965 by Hibbard et al.2 and was subsequently substantiated in several randomized controlled trials which demonstrated the effectiveness of folic acid supplementation during periconception in preventing the first occurrence of NTDs.3 These findings resulted in a recommendation in 1992 by the U.S. Public Health Service that WTA consume 400 μg of folic acid daily to prevent occurrence of an NTD-affected pregnancy.4 This recommendation together with other large-scale, global intervention studies demonstrated the efficacy of a daily periconceptional supplement of 400 μg in preventing a large percentage of NTDs.5&#x0D; Folic acid is a synthetic, oxidized form of folate that acts as a coenzyme in the biosynthesis of DNA and RNA. With 4 mg folic acid daily, it may take 20 weeks to reach red-blood-cell folate levels between 1050 and 1340 nmol/L, which is optimal for reduction of the neural tube defect risk. Therefore, folic acid supplementation should be started 5–6 months before conception. The residual risk with optimal red-blood-cell folate levels is reportedly 4.5 per 10,000 total births whereas the residual risk in pooled data from countries with mandatory folic acid fortification is 7.5 per 10,000 pregnancies, regardless of pre-fortification rates.6 In one study, the optimal RBC folate level was achieved in 80.4% of women who started FA 400 μg 4–8 weeks before their last menstrual period (LMP) compared to only 53.6% in women who started 4–8 weeks after their LMP (P &lt; 0.001). 7 A worldwide survey of folic acid supplementation in WRA showed inadequate compliance to folic acid intake.8 A systematic review and meta-analysis of pooled prevalence estimates of folic acid compliance showed 32–51% in North America, 9–78% in Europe, 21–46% in Asia, 4–34% in the Middle East, 32–39% in Australia/New Zealand, and 0% in Africa. Poor compliance was secondary to many factors. In the United States, the recommendation of 400 μg supplemental intake of folic acid daily has limitations as many pregnancies, including up to 50% of all pregnancies are unplanned.9 In many countries, particularly among low- and middle-income countries, many barriers exist for the access of WRA to folic acid supplements, such as procurement of the micronutrients in a relatively costly prepackaged form and ineffective distribution system. An evaluation of NTD trends in multiple countries indicated that, regardless of form, timing, or intended target, issuing recommendations on folic acid use alone, in the absence of fortification, had no detectable impact on NTD incidence. Thus, food fortification with folic acid has been a component of national public health strategies; in particular, where folate status is insufficient and a fortifiable food vehicle, processed by a centralized industry is consumed regularly by WRA.10,11 Other factors associated with poor compliance in folic acid intake include low income, smoking during pregnancy, alcohol consumption, multiple pregnancy, geographic location, and religious beliefs. On the other hand, preconception counselling, previous infertility therapy, multivitamin intake before pregnancy, older age planned pregnancy, previous infertility therapy, and multivitamin intake before pregnancy increased compliance.12-16 Women who also believed that they had good general and obstetric health (e.g., no history of illness or miscarriage) had attitudes of not being susceptible to the health consequences of not taking folic acid supplements and were the low users of folic acid supplement.17&#x0D; In the Philippines, although WRA are advised to consume 320 ug dietary folate equivalent per day,18 about 0.9 % (around 1 in 5) are folate-deficient based on red cell folate count, while 38.7% (around 2 in 5) are folate-deficient based on serum folate.19 Congenital malformations including NTDs remain in the top ten leading causes of infant mortality from 1960 to 2005.20 In the index paper of Bernardo21 a cross-sectional, cluster sampling survey of 184 healthy, pregnant women, of age 15–49 years was conducted in the Batangas province from May to July 2017 to assess the level of knowledge, attitude, and perceived practice among the subjects on the importance of folate periconceptionally. A pretested interview questionnaire was used. The mean scores were 77% (moderate level) for knowledge, 82% for positive attitude, and 71% for positive perceived practice. The scores in the survey were related to patient’s age, civil status and to some extent, education. The study suggested that while respondents knew about folate (70%), they had low knowledge of the effect of its deficiency especially as it can lead to infant death. Knowledge had significant and positive moderate correlation with attitude (r = 0.7) and perceived practice (r = 0.5), but there was a weak positive correlation between attitude and perceived practice (r = 0.4). This likely indicates failure to emphasize the translation of knowledge and awareness properly and sufficiently into actual practice. As recommended by the author, education is the principal means to achieve the desired outcome. However, it is not clear in the study whether some amount of educational intervention besides determination of prevalence was included. As in any prevalence study, the golden opportunity to improve health outcomes is to accompany the survey with educational intervention, which in many instances, is required by the institutional board review. Some regression analysis of the data may also have been useful to determine which factors contributed most to the outcome measures.&#x0D; &#x0D; Enrique M. Ostrea, Jr., MD Wayne State University Hutzel Women’s Hospital Children’s Hospital of Michigan Detroit, Michigan, United States of America; National Institutes of Health University of the Philippines, Manila&#x0D; &#x0D; REFERENCES &#x0D; &#x0D; Blencowe H, Kancherla V, Moorthie S, Darlison D, Modell B. Estimates of global and regional prevalence of neural tube defects for 2015: a systematic analysis. Ann NY Acad Sci. 2018; 1414:31-46.&#x0D; &#x0D; &#x0D; Hibbard B, Hibbard E, Jeffcoate J. Folic acid and reproduction. Acta Obstet Gynecol Scand. 1965; 44:375-400.&#x0D; &#x0D; &#x0D; MRC Vitamin Study Research Group. Prevention of neural tube defects: Results of the Medical Research Council Vitamin Study. Lancet 1991; 338:131-7.&#x0D; &#x0D; &#x0D; Centers for Disease Control and Prevention. Recommendations for the use of folic acid to reduce the number of cases of spina bifida and other neural tube defects. MMWR Recomm Rep. 1992; 11:1-7.&#x0D; &#x0D; &#x0D; Berry R, Li Z, Erickson J, Li S, Moore C, Wang H, et al. Prevention of neural-tube defects with folic acid in China. N Engl J Med. 1999; 341:1485-890.&#x0D; &#x0D; &#x0D; Cawley S, McCartney D, Woodside J, Sweeney M, McDonnell R, Molloy A, et al. Optimization of folic acid supplementation in the prevention of neural tube defects. J Public Health (Oxf ). 2018; 40:827-34.&#x0D; &#x0D; &#x0D; van Gool J, Hirche H, Lax H, De Schaepdrijver L. Folic acid and primary prevention of neural tube defects: A review. Reprod Toxicol. 2018; 80:73-84.&#x0D; &#x0D; &#x0D; Crider K, Bailey L, Berry R. Folic acid food fortification: Its history, effect, concerns and future directions. Nutrients. 2011; 3:370-84.&#x0D; &#x0D; &#x0D; Finer L, Henshaw S. Disparities in rates of unintended pregnancy in the United States, 1994 and 2001. Perspect Sex Reprod. Health. 2006;38: 90-6.&#x0D; &#x0D; &#x0D; Botto L, Lisi A, Robert-Gnansia E, Erickson Stein J, Vollset E, Mastroiacovo P, et al. International retrospective cohort study of neural tube defects in relation to folic acid recommendations: are the recommendations working? BMJ 2005; 330: 571.&#x0D; &#x0D; &#x0D; Garrett G, Bailey L. A public health approach for preventing neural tube defects: Folic acid fortification and beyond. Ann N Y Acad Sci. 2018; 1414:47-58.&#x0D; &#x0D; &#x0D; Forster D, Wills G, Denning A, Bolger M. The use of folic acid and other vitamins before and during pregnancy in a group of women in Melbourne, Australia. Midwifery. 2009; 25:134-46.&#x0D; &#x0D; &#x0D; Tamirat K, Kebede F, Gonete T, Tessema G, Tessema Z. Geographical variations and determinants of iron and folic acid supplementation during pregnancy in Ethiopia: Analysis of 2019 mini demographic and health survey. BMC Pregnancy Childbirth. 2022; 22:127.&#x0D; &#x0D; &#x0D; De Santis M, Quattrocchi T, Mappa I, Spagnuolo T, Licameli A, Chiaradia G, De Luca C. Folic acid use in planned pregnancy: an Italian survey. Matern Child Health J. 2013; 17:661-6.&#x0D; &#x0D; &#x0D; Felipe-Dimog E, Yu C, Ho C, Liang F. Factors influencing the compliance of pregnant women with iron and folic acid supplementation in the Philippines. 2017 Philippine Demographic and Health Survey Analysis. Nutrients. 2021; 13: 3060.1-9.&#x0D; &#x0D; &#x0D; Toivonen K, Lacroix E, Flynn M, Ronksley P, Oinonen K, Metcalfe A, et al. Folic acid supplementation during the preconception period: A systematic review and meta-analysis. Prev Med. 2018; 114:1-17.&#x0D; &#x0D; &#x0D; Fulford B, Macklon N, Boivin J. Mental models of pregnancy may explain low adherence to folic acid supplementation guidelines: a cross-sectional international survey. Eur J Obstet Gynecol Reprod Biol. 2014 May; 176:99-103.&#x0D; &#x0D

The rise and fall of blood folate in the United States emphasizes the need to identify all sources of folic acid

Fruit, Vegetables, and Folate: Cultivating the Evidence for Cancer Prevention

Neural tube defects and folic acid in Japan: Prologue introduction ‐ Understanding of the current status of Japan and the proposal from Japanese Teratology Society

To summarize the recommendations on folate intake and folic acid supplementation and fortification in the periconceptional period, aimed at prevention of neural tube defects (NTD), provided by official health organizations in different countries worldwide and WHO. Information on recommendations for folate and folic acid intake in the periconceptional period was gathered from the websites of official national health organizations of several countries worldwide and from the WHO website. WHO, selected developed countries and emerging economies, totalling thirty-six countries worldwide (some European, BRICS, G8, Asian Tiger/Asian Dragon and Australia). Recommendations differ between countries, although the majority (69·4 %) recommend a healthy diet plus a folic acid supplement of 400 µg/d from preconception (4-12 weeks) until the end of the first trimester of pregnancy (8-12 weeks). The same recommendation is issued by the WHO. Dosages for women at high risk of NTD are up to 4-5 mg/d (for 41·7 % of studied countries). The recommended intake for folate is in the range of 300-400 µg/d for women of childbearing age and 500-600 µg/d for pregnant women in different countries and WHO. Five countries emphasize the importance of a healthy diet rendering supplementation needless. By contrast, five others advise a healthy diet and supplementation plus mandatory fortification. Only one mentions the importance of ensuring an adequate folate status and refers to checking with a health-care provider on the need for supplements. Different recommendations regarding folate and folic acid, seeking NTD prevention, are available worldwide; however, most countries and WHO focus on a healthy diet and folic acid supplementation of 400 µg/d periconceptionally.

DNA methylation is an epigenetic mechanism that regulates gene expression and can be modified by one-carbon nutrients. The objective of this study was to investigate the impact of folic acid (FA) fortification of the US food supply on leukocyte global DNA methylation and the relationship between DNA methylation, red blood cell (RBC) folate, and other one-carbon biomarkers among postmenopausal women enrolled in the Women's Health Initiative Observational Study. We selected 408 women from the highest and lowest tertiles of RBC folate distribution matching on age and timing of the baseline blood draw, which spanned the pre- (1994–1995), peri- (1996–1997), or post-fortification (1998) periods. Global DNA methylation was assessed by liquid chromatography-tandem mass spectrometry and expressed as a percentage of total cytosine. We observed an interaction (P = 0.02) between fortification period and RBC folate in relation to DNA methylation. Women with higher (vs. lower) RBC folate had higher mean DNA methylation (5.12 vs. 4.99%; P = 0.05) in the pre-fortification period, but lower (4.95 vs. 5.16%; P = 0.03) DNA methylation in the post-fortification period. We also observed significant correlations between one-carbon biomarkers and DNA methylation in the pre-fortification period, but not in the peri- or post-fortification period. The correlation between plasma homocysteine and DNA methylation was reversed from an inverse relationship during the pre-fortification period to a positive relationship during the post-fortification period. Our data suggest that (1) during FA fortification, higher RBC folate status is associated with a reduction in leukocyte global DNA methylation among postmenopausal women and; (2) the relationship between one-carbon biomarkers and global DNA methylation is dependent on folate availability.