Abstract
Firm evidence from randomized, controlled trials that maternal periconceptional folic acid reduced the risk of neural-tube defects was published in the early 1990s. Despite promotion of periconceptional folic acid supplement use, no more than 50% of women take them and so mandatory fortification of a staple food has been considered by many countries as an important adjunct to any public-health approach for the prevention of neural-tube defects. Even 15 years after the confirming evidence, some countries have yet to commit to mandatory fortification and, in those that have, there is limited and poorly coordinated monitoring and evaluation of its effectiveness and safety.
Keywords
In the early 1990s, two randomized, controlled trials were published that provided strong evidence of the prevention of neural-tube defects by periconceptional folic acid supplementation [1,2]. One trial addressed recurrence of neural-tube defects (with a dose of 4 mg folic acid daily) [1] and the other the first occurrence of a neural-tube defect (with a dose of 0.8 mg folic acid daily) [2]. The trial data confirmed the findings of many prior observational studies, most of which examined the effect of folic acid supplement use (usually 0.4 mg or less daily), while some of them also looked at dietary intake [3]. This was a milestone in birth defects prevention – opportunities for preventing birth defects are few and far between and neural-tube defects are abnormalities that carry high mortality and, in survivors, lifetime disability. The preventive message was deceptively simple – sufficient folate before and in early pregnancy would prevent up to 70% of neural-tube defects [3]. Folate (a generic term for the water-soluble B-vitamin that is essential by virtue of its role in metabolism of nucleic and amino acids) is found especially in leafy green vegetables, whole-grain cereals, pulses, nuts and many fruits and other vegetables. Although most women's diets do not contain a large amount of natural food folate, folic acid (a synthetic form of the vitamin) can also be taken as a supplement, which in most countries is cheap and available over the counter. Food folate has approximately half the bioavailability of folic acid. The main barrier to prevention lies in the fact that the neural tube closes very early in pregnancy – by the end of the sixth week after the last menstrual period – and often before a woman knows for sure that she is pregnant. Thus, and especially if a pregnancy is unplanned, a woman may not increase her folate intake until the pregnancy is confirmed, which may be too late to provide protection against neural-tube defects. Mandatory fortification with folic acid of a commonly eaten foodstuff (e.g., flour or bread) was seen as a means to overcome this barrier. Women consuming the fortified food would passively have an increased intake of folate, whether or not their pregnancy was planned and, hence, would have added protection against the development of a neural-tube defect in their fetus. Another compelling reason for mandatory fortification is the fact that, even with vigorous public-health efforts to promote periconceptional folic acid supplement use for the prevention of neural-tube defects, the message is taken up by no more than half of the target population [4]. What is more, there is good evidence that the health promotion message does not reach all segments of the target population equally. Women who take periconceptional folic acid supplements are more likely than nontakers to be older, married, better educated, have planned their pregnancy, be non-smokers and to engage in other health-promoting behaviors [4,5]. As an inverse social class gradient has been found for neural-tube defects [6], the women at highest risk may be the ones most likely not to be taking periconceptional supplements.
Bringing these inequities into sharp relief are data from Western Australia showing a widening gap between neural-tube defect rates in Indigenous and non-Indigenous infants. In the 1980s, prior to confirmation that folate helped prevent these defects (and hence before any promotion of periconceptional folate for their prevention), neural-tube defects were shown to be 40% more common amongst Indigenous compared with non-Indigenous infants in Western Australia [7]. Promotion of folic acid supplements has been undertaken in Western Australia since late 1992 and voluntary fortification (of a limited number of foods in Australia, mostly breakfast cereals) was instituted in 1996 [8,9]. Since then, there has been a 30% decline in the prevalence of neural-tube defects in non-Indigenous infants but no change for Indigenous infants, such that Indigenous infants are now twice as likely to have a neural-tube defects compared with non-Indigenous infants [10].
It is for these reasons that mandatory fortification has such appeal. Many countries have instituted such fortification, usually of flour (
Countries and regions where mandatory fortification of flour with folic acid has been undertaken.
Milligrams of folic acid added or minimum level of folic acid required per kg of wheat flour.
Maize meal also fortified 2.21 mg/kg. From [103].
The effect of fortification on the prevalence of neural-tube defects has been assessed using data from the USA, Chile and Canada (
Prevention of neural-tube defects with mandatory fortification of food with folic acid.
Ratio of prevalence of neural-tube defects postfortification over prevalence of neural-tube defects prefortification.
Calculated from data supplied in [31].
CI: Confidence interval.
There are three main arguments proposed against mandatory fortification. The first is that it is mass medication of the entire population for the benefit of very few. The second is concern over possible risks of a population increase in folate intake and the third relates to issues of choice.
With respect to the mass medication argument – most public-health programs are applied to all or most of the population for the benefit of many fewer. An analogy in the birth defects field is that of rubella vaccination. Rubella is usually a mild exanthematous infection but when contracted by a pregnant woman can lead to severe birth defects in the fetus. We vaccinate the whole population (males and females) against rubella to prevent pregnant women contracting the disease during pregnancy and exposing their fetus to the infection. Why this difference in attitude to prevention? Lack of familiarity with neural-tube defects may be a reason – because of the high early mortality rate and the opportunity for prenatal diagnosis and termination of pregnancy, survivors with this condition are relatively few in number. However, before mass vaccination, congenital rubella syndrome was less than half as common as neural-tube defects in Australia, even at the peak of rubella epidemics [11]. Familiarity with and acceptance of vaccinations in general could be another reason, although many countries also have forms of food fortification that appear to be well-accepted (e.g., iodine and thiamine).
Related to the mass medication argument is the contention that neural-tube defects occur because of a genetic abnormality of folate metabolism in a small number of people (rather than a simple insufficiency of folate intake). The solution proposed by this line of reasoning is to identify those people with the genetic abnormality and for only them to take folic acid supplements. Whilst this has some appeal, research on the genetics of folate metabolism has so far failed to identify sound evidence of genetic clues that would differentiate sufficient numbers of people at increased risk to have a population-wide impact on neural-tube defect occurrence [12]. Such an approach would also require genetic testing of the entire population of women of child-bearing age.
The major potential risks of fortification that have been raised are masking of vitamin B12 deficiency, interactions with anti-epileptic treatments, potentiation of some cancers and an increase in twinning. It is vital that the benefits and risks of any public-health intervention be carefully weighed. Studies from Canada and the USA in relation to fortification in those countries have not found an increase in B12 deficiency in the absence of low folate, nor any effect on serum concentrations of anti-epileptic drugs [13–15]. In both of these situations, the possible effects of increased folate from whatever source (diet, supplements or fortified food) may require clinical attention but are not reasons to avoid fortification. The possible increase in cancer with increasing folate [16–18] is of more concern at a population level. At this stage, the risk is theoretical and there is no empirical evidence for an increase in countries with mandatory fortification. There is also evidence of a protective effect of folate against some cancers [17]. The possible increase in multiple births is an issue of increased folate from any source in women of childbearing age, not an issue of fortification per se. Analysis of data from the randomized, controlled trials of neural-tube defect prevention with periconceptional vitamin supplementation suggested a 40% (but not statistically significant) increase in multiple births in the supplemented arms of the studies [3]. The balance of evidence, however, including from countries where fortification has already been introduced, is that there is either no increase or a very much smaller increase that may be related to causes other than folate (e.g., assisted reproduction and increased maternal age) [19–22]. A recent report from the UK Scientific Advisory Committee on Nutrition (SACN) of folate and disease prevention includes a comprehensive review of these possible adverse effects of folic acid [101]. SACN recommended ‘mandatory fortification of flour with folic acid as the most effective way to increase folate intakes of women most at risk of neural-tube defect-affected pregnancies’.
The issue of choice is important to consider. If all flour were fortified, people wanting to avoid folic acid-fortified flour for whatever reason would not be able to do so. However, permitting the production of a small amount of unfortified flour (perhaps wholemeal flours) would be one way to accommodate individual choice at the same time as providing public-health benefit to the majority of women.
A force acting against mandatory fortification may be the food industry. Mandatory addition of folic acid to food would deprive a food company of a potential commercial advantage in promoting a product fortified voluntarily by them but not by rival companies. Moreover, unlike vaccines, folic acid is cheap to produce and relatively easy to add to flour, so fortified products may have limited commercial appeal. An example of the commercial pressure against mandatory fortification occurred in Australia in 2006, just before the Ministerial Council was to consider a proposal from Food Standards Australia New Zealand for mandatory fortification of flour with folic acid. One of Australia's largest bread manufacturers wrote to all Federal and State ministers urging them to reject the proposal and, in a media release about this on their website, states that ‘The food industry believed that a combination of voluntary fortification of a variety of foodstuffs, education and supplements were the answer to ensuring women of childbearing age met their daily folic acid requirements’. They provide no evidence to support this belief [102].
There are two further points I wish to discuss. The first relates to the considerable effort in most Western countries to provide screening for pregnant women to identify neural-tube (and other) defects antenatally and to offer termination of affected pregnancies. In the three Australian states with complete ascertainment of neural-tube defects, almost 70% of all neural-tube defects in 1999–2003 were identified prenatally and the pregnancy terminated [23]. Surely preventing the neural-tube defect occurring in the first place deserves at least as much effort as providing a screening and termination service? Yet the latter is a major state activity and/or commercial venture, whilst promotion of folate for the prevention of neural-tube defects is often poorly funded, poorly coordinated and poorly maintained.
Finally, as with any public-health intervention, mandatory fortification needs to be accompanied by a well-funded, coordinated and maintained program that monitors compliance with fortification, measures of folate status and outcomes, and is willing and able to react to new concerns. Information on compliance with fortification must be obtained, including the products fortified and the levels of fortificant in the fortified food. Of some concern is a recent paper from the USA showing falling blood levels of folate – one possible reason proposed for this is that the levels of folic acid in fortified foods may also be falling [24]. Measures of folate intake should be monitored using nutrition surveys and serum or red-cell folate levels in representative members of the target (women of child-bearing age) and nontarget populations (e.g., children and the elderly). Information needs to be collected on neural-tube defects and must include complete counts of births and terminations. Information should be collected on the other possible positive and negative outcomes that have been raised, including the increase in twinning, masking of B12 deficiency, reduction in cardiovascular disease [25] and a reduction or increase in some cancers [16]. Such data collections must precede the introduction of fortification by a sufficient period of time to be able to monitor prefortification trends to compare with those occurring postfortification. Community attitudes to fortification should also be monitored. All data need to be reviewed at regular intervals so that action can be taken should any untoward effects emerge. In USA and Canada, several (mainly research) groups have been outstanding in addressing aspects of monitoring the introduction of folic acid fortification in their respective countries. However, no coherent plan was made a priori to monitor changes in folate status, neural-tube defects or possible untoward effects [26,27]. A comprehensive evaluation of neural-tube defect rates, dietary assessment, blood analysis and assessment of knowledge and use of supplements before and after fortification was undertaken in Newfoundland, Canada [15] but it is unclear if there is to be continued monitoring of these and other possible outcomes. Although further research on the complex relationships between folate and health outcomes is necessary, it requires more than the efforts of research groups (which are frequently dependent on the exigencies of grant funding bodies) to monitor the effects of mandatory fortification. It is essential that state and national health authorities establish and maintain an independent, well-resourced, systematic and centrally coordinated program to monitor and evaluate mandatory fortification of food with folic acid.
Future perspective
In 5–10 years, there will be better characterization of the genetic predispositions to neural-tube defects, greater clarity on the gene–environment interactions and elucidation of pathways other than folate to their origin. However, it is still likely that the primary prevention of neural-tube defects will be largely through environmental means. Although new ways of increasing the proportion of women taking periconceptional folic acid supplements may be developed, the increase in intake through fortification of a staple food will still play an important public-health role in preventing neural-tube defects. Public-health monitoring and research will be alert to both positive and negative outcomes of increased folate and, as needed, will act on the findings in a timely manner.
Executive summary
Sufficient maternal folate before and in early pregnancy prevents up to 70% of neural-tube defects, yet no more than 50% of women have heeded the health-promotion message to take periconceptional folic acid supplements and the message has not reached all women equally. For this reason, mandatory fortification is appealing, although there are arguments against it, the main one of which revolves around mass medication of the entire population for the benefit of very few, and possible harm to some.
Most public-health interventions involve the whole population for the benefit of few individuals (e.g., vaccination for rubella to prevent congenital rubella syndrome) but the benefits and risks of any public-health intervention must be carefully weighed.
It is essential that, if introduced, mandatory fortification be accompanied by a well-funded, coordinated and maintained program that monitors compliance with fortification, measures of folate status and outcomes (positive and negative) and is able and willing to react to new concerns.