Folate status in the <scp>UK</scp>

One in 5 teenage girls and young women aged 16–24 years in the UK are deficient in the B vitamin folate, according to latest figures from the government's dietary survey, the National Diet and Nutrition Survey (NDNS), published in March 2015 (PHE 2015). Median blood levels are about half those in the US where flour is now fortified with folic acid, and similar to concentrations in the US in the mid-1990s prior to the introduction of fortification. Folate deficiency results in a form of anaemia and blood levels in early pregnancy predict risk of fetal neural tube defects (NTDs). Folate is a generic term for a family of compounds. Naturally occurring folates in food are a mixture of reduced mono- and polyglutamates, which are structurally relatively unstable (and thus influenced by food processing, including cooking). Folic acid, the ‘synthetic’ form of the vitamin used as a fortificant and in supplements, is a fully oxidised monoglutamate and the most chemically stable form. Folates function as cofactors for enzymes involved in one-carbon metabolism, providing one-carbon units for the formation of nucleotides necessary in the synthesis of RNA and DNA, and consequently cell division and tissue growth. In conjunction with vitamin B12, the vitamin is also essential for the normal functioning of the methionine cycle, which is responsible for both the conversion of homocysteine to methionine and the production of the universal methyl donor S-adenosylmethionine, which donates its methyl group to more than 100 methyltransferases for a wide range of substrates such as DNA, hormones, proteins, neurotransmitters and membrane phospholipids, all of which are regulators of important physiological processes (SACN 2006; EFSA 2015). Folate deficiency impairs DNA replication, adversely affecting rapidly proliferating tissues such as bone marrow and resulting in the production of unusually large macrocytic cells with poorly differentiated nuclei that are the predominant feature of folate deficiency in megaloblastic anaemia. It has also been reported that folate deficiency is associated with structural damage to DNA as a consequence of misincorporation of uracil instead of thymine, which might have implications for cancer (EFSA 2015), and observational studies have suggested that use of folic acid is inversely associated with cancer incidence. Safety concerns emerged as two studies published in 2007 suggested that chronic ingestion of high doses of folic acid (1 mg/day or more) might increase the risk of colorectal neoplasm in people with a recent history of colorectal adenomas (Cole et al. 2007; Mason et al. 2007) or increase the risk of developing prostate cancer (Figueiredo et al. 2009). However, a recent meta-analysis of 13 randomised controlled trials including almost 50 000 participants showed that a median dose of 2 mg/day administered for an average duration of 5.2 years did not significantly increase overall or site-specific cancer incidence compared to a placebo (Vollset et al. 2013). The same conclusions were drawn in a second meta-analysis of 26 trials of the effect of folic acid supplementation on cancer and all-cause mortality lasting up to 7.3 years (Mackerras et al. 2014). The European Food Safety Authority (EFSA) noted the relatively short duration of these cancer trials but also that the folic acid intakes were at or above the currently accepted upper intake level of intake. The relationship between folic acid and cancer risk has also been reviewed by the UK's Scientific Advisory Committee on Nutrition (SACN), as discussed later. Two sensitive biomarkers of folate intake and status are serum total folate concentration and red cell folate concentration, the latter being considered a better measure of longer term status as it reflects body stores at the time of red blood cell synthesis and is indicative of folate status over the 120-day lifespan of red blood cells, whereas serum total folate concentration responds rapidly to change in dietary intake. In the NDNS, less than 3% of children aged 4–10 years had a serum total folate concentration below the World Health Organization (WHO) threshold indicating biochemical folate deficiency (10 nmol/l) but a substantial proportion of adolescents aged 11–18 years (16.9% of boys and 21.8% of girls) had low serum total folate concentrations (Table 1), i.e. below this threshold. There was also evidence of deficiency in 14.7% of adults aged 19–64 years (15.5% men, 13.9% women) and 10.8% of adults aged 65 years and over (8.5% men and 12.4% women). For red blood cell folate, less than 4% of children aged 4–10 years were below the WHO threshold indicating biochemical folate deficiency (340 nmol/l) but substantially more girls (19.7%) than boys (9.3%) aged 11–18 years were affected. Low levels were also evident in adults but the prevalence was lower than in teenagers (Table 1). Serum total folate concentrations were significantly lower in adults aged 19–64 years in Scotland and Northern Ireland compared to the UK as a whole. In Wales, the mean concentration was significantly lower for adults aged 65 years and over, but the proportion below the WHO threshold of 10 nmol/l was similar (12.4% in Wales vs. 10.7% in the UK as a whole). Among those aged 11–18 years in Scotland, 23% of boys and 23.6% of girls had a serum folate below the WHO threshold. In Northern Ireland, the percentages were 17.4% and 19.6%, and in Wales 20.3% were below the 10 nmol/l threshold. Again for red blood cell folate, in Scotland, a greater proportion of women aged 19–64 years (13.9%) and adults aged 65 years and over (16.5%) were below the WHO threshold for deficiency compared to the UK as a whole (8.6% and 9.3% respectively). In Northern Ireland, mean red blood cell folate concentration was significantly lower among women aged 19–64 years and adults aged 19–64 years (males and females combined) compared to the UK as a whole. There were no significant differences between Wales and the UK as a whole for any age group. There is evidence of an increased risk of folate deficiency for a considerable proportion of women of childbearing age. The percentage of women with a serum total folate concentration below the threshold for biochemical deficiency was highest in UK women aged 16–24 years (22.1%), followed by women aged 25–34 years (17.7%) and was evident in 13.1% of women aged 35–49 years (PHE 2015). The percentage of women of childbearing age with a red blood cell folate concentration below 340 nmol/l was highest among those aged 16–24 years (15.6%) and lowest for those aged 25–34 years (9.5%) (PHE 2015). A greater proportion of women of childbearing age had serum total folate below the WHO threshold in Scotland (24.4%) and Northern Ireland (30.6%) compared to the UK as a whole (16.5%). The figure for Wales (14.5%) was not significantly different to the UK average. The proportion of women of childbearing age with a red blood cell folate concentration below the WHO threshold for deficiency was again greater in Scotland (14.8%) and Northern Ireland (20.2%) compared to the UK as a whole (11.3%). The proportion in Wales (10.3%) was similar to the UK average. Given the recognised importance of folate status during pregnancy, WHO is consulting on whether there should be specific folate status thresholds for women of childbearing age, in light of the risk of NTDs. In summary, folate functions together with vitamin B12 to form healthy red blood cells. It is also required for normal cell division, the normal structure of the nervous system and specifically in the development of the neural tube (which develops into the spinal cord and skull) in the embryo. Periconceptional supplementation with folic acid has a well-established protective role against both first occurrence and recurrence of NTDs (anencephaly and spina bifida) resulting in worldwide consensus on recommendations for the prevention of the first occurrence of an NTD, which are that women of childbearing age should consume supplemental folic acid at a dose of 400 μg/day for at least one month before and during the first trimester, in addition to consuming food folate from a varied diet (SACN 2006; SACN 2009; EFSA 2015). The high prevalence of folate deficiency in adolescents, particularly among girls and young women, is particularly concerning as it means that many young women may enter pregnancy in a depleted state. Folate status in the early stages of pregnancy predicts risk of fetal NTDs and folate requirements are increased during pregnancy. It is difficult to meet the increased folate requirements during pregnancy from food alone, and so all women of childbearing age who are planning a pregnancy are recommended to take a supplement of 400 μg folic acid per day (and should continue to take this for the first 12 weeks of pregnancy) to prevent NTDs in the baby (SACN 2006; EFSA 2015) but adherence to the advice in the UK is limited. For example, in the Southampton Women's Survey, only 2.9% complied fully with pre-pregnancy recommendations to take folic acid (Inskip et al. 2009) and in any case many pregnancies are unplanned. As is evident from Table 2, teenage girls have an average intake of just 186 μg/day; 8% of this age group have intakes below the lower reference nutrient intake (LRNI) (the amount adequate for only 2.5% of the population). Naturally occurring folates are found in most fruits and vegetables in small amounts but the principal sources are green leafy vegetables (e.g. spinach, kale and Brussels sprouts), legumes, orange juice, liver, peanuts, almonds, yeast extract and fortified breakfast cereals. Potatoes and milk also contribute owing to the amounts consumed (Table 2). Cereals and cereal products are the largest contributor in the UK, for all age groups, the largest amounts coming from breakfast cereals (some of which are voluntarily fortified with folic acid) and bread. Vegetables and potatoes (including potato products) are also quantitatively important sources. Milk and milk products provided 19% of folate intake for children aged 1.5–3 years. Currently, folic acid and calcium-L-methylfolate can be added to foods and food supplements in Europe, and recently the safety of 5-methyl-tetrahydrofolate glucosamine salt received a favourable opinion from EFSA at proposed levels of up to 1.8 mg/day (equivalent to 1 mg 5-methyl-tetrahydrofolate) but it has yet to be authorised for addition to food supplements (EFSA 2015). In many parts of the world, though not Europe, flour is fortified with folic acid to ensure adequate intakes. As a result of the mandatory folic acid fortification policy introduced in North America, designed to provide an additional 100 μg/day of folic acid (170 μg dietary folate equivalents/day), the NTD incidence has declined by 27% and 50% respectively in the US and Canada (EFSA 2015). In 2006, the UK government advisory committee known as SACN recommended the introduction of mandatory fortification of folic acid, accompanied by controls on voluntary fortification. In the meantime, concern was growing about a possible link between folic acid and cancer risk (Cole et al. 2007; Mason et al. 2007; Figueiredo et al. 2009). In response to a request from the Chief Medical Officer for a detailed consideration of this purported link, in 2009 SACN upheld its advice on mandatory fortification (coupled with controls on voluntary fortification) but amended advice regarding supplement use by particular population groups (SACN 2009). The UK government has yet to take a decision on whether mandatory fortification of bread and flour with folic acid should be implemented in the UK. Since the time of SACN's review of the evidence in 2006, a number of countries have published revised reference values for folate. Most recently, in February 2015 EFSA published its scientific opinion, increasing the dietary reference values for folate compared to the previous Scientific Committee for Food values. See Table 3 for a comparison of the new EFSA values with those from other authorities. The proposals from EFSA are based on the average requirement needed to maintain folate adequacy characterised by serum and red blood cell folate concentrations of ≥10 nmol/l and ≥340 nmol/l, respectively (i.e. the WHO thresholds referred to above). The population reference intake (PRI) assumes a coefficient of variation of 15% to take account of the additional variability associated with the higher requirement for folate in individuals with the methylene-tetrahydrofolate reductase (MTHFR) 677TT genotype. The EFSA values for infants aged 7–11 months are extrapolated from the estimated intake of exclusively breastfed infants. For children, the average requirements are extrapolated from the values for adults. The evidence on folate status underlines the concern that exists about the diets of young people, especially young girls and women. The NDNS makes it plain that many young women have a nutrient-poor diet and could eat better, exemplified by low intakes (compared to the LRNI) of iron in almost 50% and riboflavin, calcium, iodine and zinc in 20%. Among females, those aged 11–24 years have the highest free sugars intakes (reaching 15.8% of calorie intake in 16–24 year-olds compared to 10.2% in 50–64 year-olds). This age group also has the lowest fibre intakes and barely 10% achieve five portions of fruit and vegetables a day. So there is a need to focus on the full basket of healthy eating messages, stressing micronutrient dense foods as well as moderation in intakes of sugars, salt and saturated fatty acids. So, some of the worst diets are consumed by teenagers and young adults: the next generation of parents. It is worth noting that although teenage pregnancy rates, historically the highest in Europe, have now fallen considerably (pregnancies in 15–17 year-olds have almost halved in the past 15 years), there are still 24.5/1000 conceptions in girls aged under 18 years (ONS 2015). The inter-generational effects of nutrition during pregnancy are now recognised – the nutritional status of young women today may affect the health of their grandchildren. The importance of nutrition pre-conception is being emphasised and word is getting out that entering pregnancy obese is not good for mother or child. Balancing dietary energy density and nutrient density is challenging and young people are considered ‘hard to reach’ with health messages, but there are real opportunities for the food industry to use its skills to innovate and guide young people down a healthier dietary path that is conducive to maintaining a healthy weight and delivering good nutrition.

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