Please refer to anzfa’s guide to applications and proposals for a more detailed explanation of the process on how to undertake

A recently published paper suggests that a higher folate status during the peri-conceptional period could select embryos that carry a particular gene associated with a range of developmental and degenerative conditions. An increase in folate status arising from population-based approaches such as fortification, may therefore increase the proportion of individuals with these genes, and in time, increase the population’s dependency on future folate fortification (Lucock and Yates, 2005).
FSANZ has not been able to identify any other study or article that investigates the potential for increased population folic acid intakes to select for particular genetic traits.

11. Summary of the benefits and risks associated with increased folic acid intake

The above discussion highlights several potential risks and benefits from increased folic acid intakes. However, there are also a number of areas in the scientific literature where the outcomes are contradictory and as yet undefined, or inconclusive due to the lack of available evidence.

11.1 Potential health benefits

There is strong evidence from other countries that have introduced mandatory fortification that increases in intake of folic acid up to 200 µg/day are associated with significant reductions in the incidence of NTDs. The extent of the fall in incidence appears to depend on the prevailing background rate of NTDs prior to fortification.

An increased intake of folic acid is associated with a reduction in serum tHcy, which has been recognised as a biomarker of increased risk of cardiovascular disease.

More recent studies, however, demonstrate that an increased folic acid intake does not reduce the risk of cardiovascular disease in individuals who had experienced a prior cardiovascular event, despite a concurrent reduction in tHcy levels. Thus the current evidence base does not support an association between increased folic acid intake and reduced risk of cardiovascular disease.

11.2 Potential health risks

It is recognised that excessive intakes of folic acid may mask the diagnosis of vitamin B₁₂ deficiency potentially resulting in neurologic damage. However, the available evidence indicates that folic acid intakes up to 1 mg/day (the adult UL) will not mask the diagnosis of vitamin B₁₂ deficiency. The relevance of the UL for younger age groups, particularly children, is unclear because vitamin B₁₂ deficiency is rare in children.

Although there is the potential for increased folic acid intake to interfere with certain medications, the available scientific evidence has not demonstrated any clinically significant interaction with therapeutic medicines from folate intakes up to 1 mg/day.
Two large trials using much higher doses of folic acid than is proposed under mandatory fortification do not indicate a gradient of risk for total cancers. For the three specific cancer sites examined, the results of more recent studies do not alter the conclusion reached in earlier reviews (SACN, 2004; SACN, 2005; Sanjoaquin et al., 2005a) that there is no apparent increase in risk associated with higher folic acid intakes for the population as a whole. Although many of the studies, in fact, suggest that some reduction in cancer might occur, most of these are observational and so might be affected by uncontrolled confounding by other factors.

11.3 Areas of uncertainty in the scientific literature

The evidence for an association between folic acid and increased risk of multiple births remains inconclusive despite the biological plausibility that folic acid could support foetal growth and development.

Improvements in cognitive function, considered in early literature as a potential positive benefit associated with increased folic acid intakes, has not been confirmed with more recent and robust scientific investigation. Therefore, the current level of evidence remains inconclusive on the role of folic acid in cognitive functioning.
The evidence is also inconclusive for a positive effect on birth weight or Down Syndrome from increased folic acid intake.
The potential impact of an increased intake of synthetic folic acid on unmetabolised circulating folic acid and on the gene pool is only just emerging in the scientific literature. The scientific discussion around these matters is not yet well developed, and cannot therefore be used in an informative assessment of the risks and benefits associated with folate fortification.

References

GLOSSARY

Anencephaly	A condition characterised by a failure of the anterior neural tube to close, resulting in the total or partial absence of the cranial vault and brain tissue. Together, spina bifida and anencephaly account for 90% of all cases of NTDs.
Bioavailability	A measure of the body’s ability to extract, absorb and metabolise a nutrient expressed as a proportion of the amount in food or supplements.
Birth prevalence of NTDs	The number of live births and stillbirths affected by an NTD expressed as a rate per 1,000 total births.
Dietary folate	The term used to refer to folate that is consumed via the diet, both naturally occurring and folic acid added through fortification. This term does not encompass folate consumed through supplements.
Dietary Folate Equivalents (DFEs)	DFEs is a term used to accommodate the various bioavailabilities of folate. One µg DFE = 1 µg food folate = 0.5 µg of folic acid on an empty stomach = 0.6 µg of folic acid with meals.
Encephalocoele	A condition characterised by the meninges and/or brain tissue extruding through a defect in the skull. This is the least frequent of the neural tube defects (Lancaster and Hurst, 2001).
Enriched	In the Unites States, this term refers to the addition of a nutrient to a food that has been lost during the course of food processing or during normal storage and handling, up to the nutrient’s level in the food before processing, storage and handling. This process is commonly referred to as ‘restoration’ in the Australian and New Zealand context.
Estimated Average Requirement (EAR)	The EAR is the daily nutrient level estimated to meet the requirements of half the healthy individuals in a particular life stage and gender group.
Folate	Folate is a water-soluble B-group vitamin. The term folate is used generically to refer to the various forms of the vitamin, both naturally-occurring and synthetic, and its active derivatives (Department of Health, 2000).
Folic acid	Folic acid, also referred to as pteroylmono-glutamic acid (PGA), is the most common synthetic form of folate and is the form used in fortification and in the majority of supplements. As its name indicates, folic acid contains a single glutamate moiety attached to pteroic acid (Ball, 1998). Folic acid is rarely found occurring naturally in foods (NHMRC, 1995). Other forms of folate that could be used in food fortification in future include 5-methyltetrahydrofolate (5-Ch3H4PteGlu, or L-methylfolate) and mixtures of naturally occurring forms.
Fortification	‘Fortification’ or ‘enrichment’ means the addition of one or more essential nutrients to a food for the purpose of preventing or correcting a demonstrated deficiency of one or more nutrients in the population or specific population groups.
Health claim	A message that makes a direct link between eating a certain food or food component and reduced risk of a specified disease.
Homocysteine	A sulphur-containing amino acid. Plasma homocysteine concentration increases when folate or vitamin B12 is deficient.
Incidence of NTDs	The number of live births, stillbirths and terminations affected by an NTD expressed as a rate per 1,000 total births. As data on the number of terminations affected by an NTD is frequently incomplete, some authors use the term ‘prevalence’.
Megaloblastic anaemia	An anaemia in which the precursors (megaloblasts) or red blood cells in the bone marrow is impaired. These precursor cells enter the blood stream at a larger size (macrocytic) than normal blood cells, yet they contain a full complement of haemoglobin.
Naturally-occurring folate	A form of folate found in a wide variety of foods including green leafy vegetables, cereals, fruits, grains, legumes, yeast extract, and liver. The term naturally-occurring folate is used in this document, to differentiate it from folic acid added to food in fortification. Naturally-occurring folate generally contains more than one, typically five to seven, glutamate moieties attached to pteroic acid (polyglutamate) (Ball, 1998).
Neural tube defects (NTDs)	NTDs are severe congenital malformations of the central nervous system and result from the failure of the neural tube to close during early embryonic development. The two major types of NTDs are anencephaly and spina bifida.
Peri-conceptional period	Refers to the period one month before and 12 weeks after conception.
Recommended dietary intake (RDI)	The RDI is the average daily dietary intake level that is sufficient to meet the nutrient requirements of nearly all (97-98%) healthy individuals in a particular life stage and gender group.
Spina bifida	A condition whereby incomplete closure of the neural tube results in the spinal cord being exposed or protruding through a gap in the spine. Over 80% of infants born with spina bifida survive into adulthood, but can develop leg paralysis or weakness, lack of bowel or bladder control and excess fluid around the brain (hydrocephalus).
Stillbirths	The birth of a dead infant of at least 20 weeks gestational age or 400 g birthweight.
Total births	Live births + still births.
Target population	Women of child-bearing age.
Termination	Termination of pregnancy occurring before 20 weeks gestation.
Upper level of intake (UL)	The UL is referred to in this Report in relation to folic acid. The UL is the highest daily nutrient intake level likely to pose no adverse health effects to almost all individuals in the general population. As intake increases above the UL, the adverse potential risk of adverse effects increases.
Women of child-bearing age	For the purposes of this Report, in particular the dietary intake assessment, women of child-bearing age refers to women aged 16-44 years.