Mandatory folic acid fortification of wheat flour for making bread was implemented in Australia in September 2009, to improve the dietary folate status of women of child-bearing age, and help reduce the incidence of neural tube defects in the population. This paper presents estimates of folic acid intake in the target population and other subgroups of the Australian population following implementation of the mandatory folic acid fortification standard. In June/July 2010 one hundred samples from seven bread categories were purchased from around the country and individually analysed for the amount of folic acid they contained. A modification to the triple enzyme microbiological method was used to measure folic acid in the individual bread samples. The folic acid analytical values together with national food consumption data were used to generate estimates of the population's folic acid intake from fortified foods. Food Standards Australia New Zealand's (FSANZ) custom-built dietary modelling program (DIAMOND) was used for the estimates. The mean amount of folic acid found in white bread was 200 μg/100 g which demonstrated that folic-acid-fortified wheat flour was used to bake the bread. The intake estimates indicated an increase in mean folic acid intake of 159 μg per day for the target group. Other sub-groups of the population also showed increases in estimated mean daily intake of folic acid.
In 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.
The 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).
Median 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).
Folate 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.
Folate has received international attention regarding its role in the risk-reduction of birth defects, specifically neural tube defects (NTDs). In 1998, health officials in Canada, like the United States, mandated the addition of folic acid to white flour and select grain products to increase the folate intake of reproductive-aged women. Subsequent to this initiative there has been an increase in blood folate concentrations in Canada and a 50% reduction in NTDs. Many countries, including Korea, have not mandated folic acid fortification of their food supply. Reasons vary but often include concern over the masking of vitamin B12 deficiency, a belief that folate intakes among womenare adequate, low priority relative to other domestic issues, and the philosophy that individuals have the right not to consume supplemental folic acid if they so choose. Prior to folic acid fortification of the food supply in Canada, the folate intakes of women were low, and their blood folate concentrations while not sufficiently low to produce overt signs of folate deficiency (eg. anemia) were inconsistent with a level known to reduce the risk of an NTD-affected pregnancy. The purpose of this article is to describe the role of folate during the periconceptional period, pregnancy, and during lactation. The rationale for, and history of recommending folic acid-containing supplements during the periconceptional period and pregnancy is described as is folic acid fortification of the food supply. The impact of folic acid fortification in Canada is discussed, and unresolved issues associated with this policy described. While the incidence of NTDs in Canada pre-folic acid fortification were seemingly higherthan that of Korea today, blood folate levels of Korean women are strikingly similar. We will briefly explore these parallels in an attempt to understand whether folic acid fortification of the food supply in Korea might be worth consideration
Folic acid; fortification; periconceptional period; pregnancy; lactation
Folate is a generic term for a water-soluble B-complex vitamin which plays an important role in protein synthesis and metabolism and other processes related to cell multiplication and tissue growth. Pregnant and lactating women are at increased risk of folic acid deficiency because generally their dietary folate is insufficient to meet their physiological requirements and the metabolic demands of the growing fetus. The evidence pertaining to the reduction of the risk of neural tube defects (NTDs) due to folate is so compelling that supplementation with 400 μg of folic acid to all women trying to conceive until 12 weeks of pregnancy has been recommended by every relevant authority. A recent Cochrane review has also found protective effects of folate supplementation in occurrence and reoccurrence of NTDs. Despite food fortification and targeted public health campaigns promoting folic acid supplementation, 4,300,000 new cases occur each year worldwide resulting in an estimated 41,000 deaths and 2.3 million disability-adjusted life years (DALYS). This article will review the burden and risk factors of NTDS, and the role of folate in preventing NTDs. It will also describe different modes of supplementing folate and the newer evidence of the effectiveness of adding folate in oral contraceptives for raising serum and red blood cell folate levels.
folate; folate-containing oral contraceptives; oral contraceptives; contraceptives
QUESTION: I read last year that Canada has followed the United States in fortifying flour with folic acid to prevent neural tube defects. Do we know yet whether this strategy is working? ANSWER: In Canada, flour is fortified with folic acid to a level of 0.15 mg/100 g. Although a mandatory date was set for November 1, 1998, most if not all companies implemented the change on or before January 1, 1998. Recent figures from the United States, where the deadline for fortification was January 1998, show that by March 1999, mean folate levels in flour doubled, substantially decreasing the risk for neural tube defects.
The vitamin folate is recognized as beneficial health-wise in the prevention of neural tube defects, anemia, cardiovascular diseases, poor cognitive performance, and some forms of cancer. However, suboptimal dietary folate intake has been reported in a number of countries. Several national health authorities have therefore introduced mandatory food fortification with synthetic folic acid, which is considered a convenient fortificant, being cost-efficient in production, more stable than natural food folate, and superior in terms of bioavailability and bioefficacy. Other countries have decided against fortification due to the ambiguous role of synthetic folic acid regarding promotion of subclinical cancers and other adverse health effects. This paper reviews recent studies on folate bioavailability after intervention with folate from food. Our conclusions were that limited folate bioavailability data are available for vegetables, fruits, cereal products, and fortified foods, and that it is difficult to evaluate the bioavailability of food folate or whether intervention with food folate improves folate status. We recommend revising the classical approach of using folic acid as a reference dose for estimating the plasma kinetics and relative bioavailability of food folate.
folate; folic acid; human bioavailability; intervention trials; post-dose plasma kinetics
Rates of neural tube defects have decreased since folic acid fortification of the food supply in the United States. The authors’ objective was to evaluate the associations between neural tube defects and maternal folic acid intake among pregnancies conceived after fortification. This is a multicenter, case-control study that uses data from the National Birth Defects Prevention Study, 1998–2003. Logistic regression was used to compute crude and adjusted odds ratios between cases and controls assessing maternal periconceptional use of folic acid and intake of dietary folic acid. Among 180 anencephalic cases, 385 spina bifida cases, and 3, 963 controls, 21.1%, 25.2%, and 26.1%, respectively, reported periconceptional use of folic acid supplements. Periconceptional supplement use did not reduce the risk of having a pregnancy affected by a neural tube defect. Maternal intake of dietary folate was not significantly associated with neural tube defects. In this study conducted among pregnancies conceived after mandatory folic acid fortification, the authors found little evidence of an association between neural tube defects and maternal folic acid intake. A possible explanation is that folic acid fortification reduced the occurrence of folic acid-sensitive neural tube defects. Further investigation is warranted to possibly identify women who remain at increased risk of preventable neural tube defects.
folic acid; neural tube defects
Primary prevention of most folate-responsive neural tube defects (NTDs) may not require 400 μg folic acid/day but may be achieved by attaining a high maternal folate status. Using RBC folate ≥906 nmol/L as a marker for NTD risk reduction, the study aimed to determine the change in blood folate concentrations in reproductive age women in response to long-term folic acid supplementation at 400 µg/day and 140 µg/day (dose designed to mimic the average daily folic acid intake received from New Zealand’s proposed mandatory bread fortification program). Participants were randomly assigned to a daily folic acid supplement of 140 µg (n = 49), 400 µg (n = 48) or placebo (n = 47) for 40 weeks. RBC folate concentrations were measured at baseline, and after 6, 12, 29 and 40 weeks. At 40 weeks, the overall prevalence of having a RBC folate <906 nmol/L decreased to 18% and 35% in the 400 µg and 140 µg groups, respectively, while remaining relatively unchanged at 58% in the placebo group. After 40 weeks, there was no evidence of a difference in RBC folate between the two treatment groups (P = 0.340), nor was there evidence of a difference in the odds of a RBC folate <906 nmol/L (P = 0.078). In conclusion, the average daily intake of folic acid received from the proposed fortification program would increase RBC folate concentrations in reproductive age women to levels associated with a low risk of NTDs.
neural tube defects; blood folate status; folic acid fortification; supplementation
The occurrence of neural tube defects (NTD) has been shown to vary by race/ethnicity, with the highest rates among women of Hispanic ethnicity. Women of reproductive age are advised to use folic acid to prevent NTD and other birth defects. Since 1994, Puerto Rico has a campaign to promote the use of folic acid and since 1998 there is fortification of enriched grain products. After fortification, there has been a reduction in the incidence of NTD in the island. The objective of this study is to assess the use of folic acid by women of reproductive age in Puerto Rico and determine factors associated to its use.
A self-administered questionnaire was answered by 964 women around the island.
Folic acid consumption was reported by 30% of the participants, 21% reported to consume it at least 4 times per week, and only 14% consumed it the day before the survey. Knowledge about the recommendation for women to consume folic acid was reported by 97% of the participants. The use of folic acid was lower among women of lower education and lower social class. Women with higher education were 8.3 times more likely to consume folic acid.
The folic acid campaign has improved women’s knowledge about the recommendation for folic acid supplementation. Nevertheless, its use is lower than desired to continue reducing the incidence of birth defects in Puerto Rico. Education and social class continue to represent barriers to eliminate the disparities in the pre-conception health of our population.
Folic acid; Birth defects; Neural tube defects
Periconceptional 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.
This 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.
The 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%.
Based 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.
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.
Neonatal mortality; folic acid; neural tube defects; pregnancy; infant; newborn; Neural Tube Defects/mortality/prevention & control; dietary supplements
QUESTION: One of my patients was diagnosed with celiac disease and maintains a strict gluten-free diet. Is her fetus at risk of neural tube defects because she does not get folic acid from bread and other flour-based foods? ANSWER: A woman with celiac disease must supplement her diet with multivitamins, including folic acid. Most prenatal vitamins contain 0.8 to 0.9 mg of folic acid, double the amount recommended by Health Canada for prevention of neural tube defects. Without supplementation (eg, undiagnosed pregnancy), women with celiac disease might not take in enough folate to maintain protective levels.
With the goal of preventing open neural tube defects (NTDs), recommendations for folic acid supplementation before conception were introduced in Canada in 1994, and by November 1998 Canadian grain products were being fortified with folic acid. We wished to determine whether the annual incidence of open NTDs in Nova Scotia, including those in stillbirths and terminated pregnancies, changed after the introduction of either folic acid supplementation or fortification.
For the 10-year period from Jan. 1, 1991, to Dec. 31, 2000, we retrospectively extracted the total number of births in Nova Scotia and the number of live births and stillbirths with open NTDs from the Nova Scotia Atlee Perinatal Database as well as the number of terminated pregnancies affected by NTDs from the Fetal Anomaly Database. We determined the total annual incidence of all open NTDs, and of the subgroups spina bifida and anencephaly, per 1000 births in the province during the periods before (1991–1994) and after (1995–1998) folic acid supplementation initiatives were begun but before folic acid fortification of grain products was implemented, and during the periods before (1991–1997) and after (1998–2000) fortification.
In the period after supplementation initiatives were begun but before fortification was implemented, the incidence of open NTDs did not change significantly: the mean annual rate was 2.55 per 1000 births during 1991–1994 and 2.61 per 1000 births during 1995–1997 (relative risk [RR] 1.02, 95% confidence interval [CI] 0.77–1.35). After the fortification was implemented the incidence of open NTDs decreased by more than 50%: the mean annual rate was 2.58 per 1000 births during 1991–1997 and 1.17 per 1000 births during 1998–2000 (relative risk 0.46, 95% CI 0.32–0.66).
The recommendations for folic acid supplementation alone did not appear to succeed in reducing the incidence of open NTDs in Nova Scotia, whereas the fortification of grain products with folic acid did result in a significant reduction in the incidence.
Periconceptional intake of folic acid is known to reduce a woman’s risk of having an infant affected by a neural tube birth defect (NTD). National programs to mandate fortification of food with folic acid have reduced the prevalence of NTDs worldwide. Uncertainty surrounding possible unintended consequences has led to concerns about higher folic acid intake and food fortification programs. This uncertainty emphasizes the need to continually monitor fortification programs for accurate measures of their effect and the ability to address concerns as they arise. This review highlights the history, effect, concerns, and future directions of folic acid food fortification programs.
folic acid; flour fortification; neural tube defects; cancer; epigenetics
Closure of the neural tube during embryogenesis is a crucial step in development of the central nervous system. Failure of this process results in neural tube defects, including spina bifida and anencephaly, which are among the most common birth defects worldwide. Maternal use of folic acid supplements reduces risk of neural tube defects but a proportion of cases are not preventable. Folic acid is thought to act through folate one-carbon metabolism, which transfers one-carbon units for methylation reactions and nucleotide biosynthesis. Hence suboptimal performance of the intervening reactions could limit the efficacy of folic acid. We hypothesized that direct supplementation with nucleotides, downstream of folate metabolism, has the potential to support neural tube closure. Therefore, in a mouse model that exhibits folic acid-resistant neural tube defects, we tested the effect of specific combinations of pyrimidine and purine nucleotide precursors and observed a significant protective effect. Labelling in whole embryo culture showed that nucleotides are taken up by the neurulating embryo and incorporated into genomic DNA. Furthermore, the mitotic index was elevated in neural folds and hindgut of treated embryos, consistent with a proposed mechanism of neural tube defect prevention through stimulation of cellular proliferation. These findings may provide an impetus for future investigations of supplemental nucleotides as a means to prevent a greater proportion of human neural tube defects than can be achieved by folic acid alone.
neural tube defects; spina bifida; embryo; nucleotides; curly tail
This paper focuses on the current best-evidence-based clinical practices and controversies surrounding folic acid supplementation/fortification for the prevention of neural tube defects (NTDs) during early pregnancy. The paper also discusses the controversies surrounding the effect of folic acid on the prevention as well as the promotion of cancer. Sufficient data is available to safely conclude that folic acid reduces the risk of NTDs during pregnancy; however, a safe dosage has not yet been calculated for the rest of the population. More research is necessary to study the complete role of folic acid in human growth and development.
Health authorities in numerous countries recommend periconceptional folic acid to pregnant women to prevent neural tube defects. The objective of this study was to examine the association of folic acid supplementation during different periods of pregnancy and of dietary folate intake with the risk of spontaneous preterm delivery (PTD).
The Norwegian Mother and Child Cohort Study is a population-based prospective cohort study. A total of 65,668 women with singleton pregnancies resulting in live births in 1999–2009 were included. Folic acid supplementation was self-reported from 26 weeks before pregnancy until week 24 during pregnancy. At gestational week 22, the women completed a food frequency questionnaire, which allowed the calculation of their average total folate intake from foods and supplements for the first 4–5 months of pregnancy. Spontaneous PTD was defined as the spontaneous onset of delivery between weeks 22+0 and 36+6 (n = 1,628).
The median total folate intake was 266 μg/d (interquartile range IQR 154–543) in the overall population and 540 μg/d (IQR 369–651) in the supplement users. Eighty-three percent reported any folic acid supplementation from <8 weeks before to 24 weeks after conception while 42% initiated folic acid supplementation before their pregnancy. Cox regression analysis showed that the amount of folate intake from the diet (hazard ratio HR 1.16; confidence interval CI 0.65-2.08) and from the folic acid supplements (HR 1.04; CI 0.95-1.13) was not significantly associated with the risk of PTD. The initiation of folic acid supplementation more than 8 weeks before conception was associated with an increased risk for PTD (HR 1.19; CI 1.05-1.34) compared to no folic acid supplementation pre-conception. There was no significant association with PTD when supplementation was initiated within 8 weeks pre-conception (HR 1.01; CI 0.88-1.16). All analyses were adjusted for maternal characteristics and socioeconomic, health and dietary variables.
Our findings do not support a protective effect of dietary folate intake or folic acid supplementation on spontaneous PTD. Pre-conceptional folic acid supplementation starting more than 8 weeks before conception was associated with an increased risk of PTD. These results require further investigation before discussing an expansion of folic acid supplementation guidelines.
Pregnancy; Preterm delivery; Preterm birth; Gestational length; Folate; Folic acid supplementation
Anti-folate chemotherapy agents such as methotrexate and fluorouracil reduce proliferation of neoplastic cells by inhibiting DNA synthesis. Paradoxically epidemiological data suggests an inverse relationship between dietary folate intake and incidence of colorectal cancer (CRC). On the basis of this and other putative health benefits around 35% of the North American population take folic acid supplements, in addition to natural food folates and fortified flour and cereal grains. Recently, randomised controlled trials investigating folic acid as a secondary preventative agent in colorectal neoplasia have shed further light on the relationship between folate and colorectal carcinogenesis, corroborating data from animal models indicating opposing effects dependent on the timing of exposure in relation to the development of neoplastic foci. A ‘dual-modulator' role for folate in colorectal carcinogenesis has been proposed in which moderate dietary increases initiated before the establishment of neoplastic foci have a protective influence, whereas excessive intake or increased intake once early lesions are established increases tumorigenesis. Functional polymorphic variants in genes encoding key enzymes in the folate metabolic pathway add a further layer of complexity to the relationship between folate and CRC risk. Here, we review the evidence concerning the efficacy and safety of folate as a potential CRC chemopreventive agent.
folate; colorectal cancer; prevention
Studies in the 1990s have found that periconceptional dietary folate, supplementation of folic acid or supplemental multivitamins containing folic acid, help prevent neural tube defect (NTDs) if taken at the right time. This literature review assesses the extant folic acid public health campaigns literature and identifies some common variables used in folic acid consumption campaign evaluations.
This review was part of a larger study that searched PUBMED, PsycINFO and Embase from 1976 to 2010 to identify articles related to the psychosocial and economic impact of NTDs (especially spina bifida) on patients and caregivers.
Awareness of folic acid levels prior to conception improved post-campaign from 6 to 41%. Knowledge about consumption and correct periconceptional use of folic acid also improved. However, in most studies more than 50% of women did not take folic acid as prescribed. Many factors were associated with or without taking folic acid post-campaign, including incomplete outreach, prior awareness and knowledge, closeness to pregnancy, demographics and other personal characteristics.
Sustained campaigning to maintain awareness about and promote periconceptional consumption of folic acid in order to reduce the incidence of NTDs is clearly needed. Additional initiatives could complement existing public health strategies.
awareness; campaigns; consumption; folic acid; knowledge
Question One of my epileptic patients who takes carbamazepine is planning to become pregnant. She told me that Motherisk advised her to take 5 mg of folic acid daily until the end of the first trimester. Are there other women who need more than the regular dose of folic acid included in prenatal vitamins?
Answer Women who are at high risk of having babies with neural tube defects and who would benefit from higher doses of folic acid include those with certain folate-enzyme genotypes, previous pregnancies with neural tube defects, diabetes, malabsorption disorders, or obesity, or those who take antifolate medications or smoke. Such women should take 5 mg/d of folic acid for the 2 months before conception and during the first trimester.
QUESTION Now that flour and pasta have been fortified with folic acid in Canada, do I still need to recommend folic acid supplements to my patients who are of child-bearing age? If I should recommend supplements, when should I recommend them, and what is an appropriate dose?
ANSWER Non-pregnant women should consume 400 μg of folic acid daily, and pregnant women should consume 600 μg of folic acid daily. Mean intakes of folate in Canada before fortification were around 200 μg/d or less. Fortification increased intake of folic acid by up to 100 μg/d. You should discuss the importance of folic acid with your patients who are planning pregnancy; it is recommended that a folic acid supplement or prenatal multivitamin containing at least 400 μg of folic acid be consumed daily. The upper limit for folic acid is 1 mg/d. Women in intermediate- to high-risk categories for neural tube defects, such as a previous neural tube defect–affected pregnancy, should take 4 to 5 mg of folic acid daily.
QUESTION The new Motherisk Guidelines suggest 5 mg/d of folic acid. Why was the dose increased? What is the time frame for taking such a dose?
ANSWER Recent data from Ontario reveal that 40% of women of reproductive age still do not achieve therapeutic systemic levels of folate needed to prevent neural tube defects. Compliance is less than optimal among women using prenatal vitamins, rendering many women unprotected against neural tube defects. Taking a higher dose of folate will allow achievement of protective folate levels, even with partial compliance. Five mg of folate should be used daily several months before conception until the end of the first trimester.
Risk of neural tube defects (NTDs) is determined by genetic and environmental factors, among which folate status appears to play a key role. However, the precise nature of the link between low folate status and NTDs is poorly understood, and it remains unclear how folic acid prevents NTDs. We investigated the effect of folate level on risk of NTDs in splotch (Sp2H) mice, which carry a mutation in Pax3. Dietary folate restriction results in reduced maternal blood folate, elevated plasma homocysteine and reduced embryonic folate content. Folate deficiency does not cause NTDs in wild-type mice, but causes a significant increase in cranial NTDs among Sp2H embryos, demonstrating a gene–environment interaction. Control treatments, in which intermediate levels of folate are supplied, suggest that NTD risk is related to embryonic folate concentration, not maternal blood folate concentration. Notably, the effect of folate deficiency appears more deleterious in female embryos than males, since defects are not prevented by exogenous folic acid. Folate-deficient embryos exhibit developmental delay and growth retardation. However, folate content normalized to protein content is appropriate for developmental stage, suggesting that folate availability places a tight limit on growth and development. Folate-deficient embryos also exhibit a reduced ratio of s-adenosylmethionine (SAM) to s-adenosylhomocysteine (SAH). This could indicate inhibition of the methylation cycle, but we did not detect any diminution in global DNA methylation, in contrast to embryos in which the methylation cycle was specifically inhibited. Hence, folate deficiency increases the risk of NTDs in genetically predisposed splotch embryos, probably via embryonic growth retardation.
There is growing evidence that optimal dietary intake of folate and choline (both involved in 1-carbon transfer or methylation) is important for successful completion of fetal development. Significant portions of the population are eating diets low in one, or both of these nutrients. Folates are important for normal neural tube closure in early gestation and the efficacy of diet fortification with folic acid in reducing incidence of neural tube defects is a major success story for public health nutrition. Similarly, maternal dietary choline is important for normal neural tube closure in the fetus and, later in gestation, also is important for neurogenesis in the fetal hippocampus with effects on memory that persist in adult offspring; higher choline intake being associated with enhanced memory performance. Though both folates and choline have many potentially independent mechanisms whereby they could influence fetal development, these two nutrients also have a common mechanism for action - altered methylation and related epigenetic effects on gene expression.
folate; choline; DNA methylation; single nucleotide polymorphism; diet requirement; brain development
Neural tube closure takes place during early embryogenesis and requires interactions between genetic and environmental factors. Failure of neural tube closure is a common congenital malformation that results in morbidity and mortality. A major clinical achievement has been the use of periconceptional folic acid supplements, which prevents ~50–75% of cases of neural tube defects. However, the mechanism underlying the beneficial effects of folic acid is far from clear. Biochemical, genetic and epidemiological observations have led to the development of the methylation hypothesis, which suggests that folic acid prevents neural tube defects by stimulating cellular methylation reactions. Exploring the methylation hypothesis could direct us towards additional strategies to prevent neural tube defects.