I gratefully acknowledge the assistance of one of my undergraduate project students, Ioana Alina Mills (nee Huci), in researching this piece.
Context of this post
Almost exactly three years ago, I confidently predicted that a government decision on whether to fortify UK flour with folic acid was imminent but there is still no clear decision. Last year, Joan Morris and colleagues estimated that if the UK had fortified flour with folic acid at the same time and level as the USA then over 2000 cases of neural tube defects NTD would have been prevented since 1998. Around 80% of these cases have resulted in a termination of the pregnancy and most of the rest in the births of severely disabled babies. In this post, I will give an up-to-date and critical review of the case for fortification.
Folic acid is the parent compound for a group of substances known collectively as folate or vitamin B9. Folic acid per se is not actually found in food but it is the form of the vitamin usually used in supplements and food fortification. Folates are important in the synthesis of a compound (thymidine) essential for DNA replication during cell division. Folate deficiency therefore affects rapidly bone marrow leading to megaloblastic anaemia characterised by large immature blood cells. Deficiency also affects other rapidly dividing tissues like gut linings and the developing embryo. A link between folate deficiency and increased risk of babies having a neural tube defect was first suggested over 60 years ago. NTD are birth defects (most commonly anencephaly and spina bifida) where the brain, spinal cord, skull and vertebral column fail to develop properly in early embryonic life. In anencephaly there is almost complete absence of skull development and these babies die in the womb or shortly after delivery. In spina bifida, the vertebral column fails to close and the spinal cord protrudes out of the back leading to a whole range of severe lifelong physical disabilities.
Clinical trials of folic acid supplements
In 1965 Richard Smithells and Elizabeth Hibbard (see ) proposed that folate deficiency or abnormal folate metabolism increased the risk of NTD. In 1991, the results of a Medical Research Council double-blind clinical trial showed conclusively that very large supplements of folic acid given from before conception and throughout early pregnancy reduced the rate of recurrence of NTD by around 70%. They recruited 2000 “high risk” women throughout Europe who had already had an affected pregnancy. Half of these women received folic acid and half did not and the recurrence rate in the folic acid groups was over 70% less than in the other groups. Lower doses of folic acid have also been shown to prevent first occurrence of NTD in non-high risk women .
Luz Maria De-Regil and her colleagues (2015) amalgamated all of the high quality clinical trials that had assessed the effect of folic acid supplements on NTD incidence. They concluded that:
- Folic acid supplements when taken from before conception and during early pregnancy substantially reduce the risk of NTD (c70% reduction)
- The presence or absence of other vitamins in the supplements makes no difference
- Supplement doses above 400µg/day offer no extra benefit (the dose currently recommended for all young UK women)
- They found no evidence that these supplements reduced the incidence of other birth defects although the evidence was low quality.
In clinical trials, supplements of folic acid greatly reduce recurrence and first occurrence of NTD and the optimal dose is 400µg/day or less.
Fortification of food with folic acid
Well over 60 countries around the world now fortify a staple food, usually wheat flour, with folic acid at doses of 100 to 300 µg/100g flour. Wherever mandatory fortification has been introduced it has resulted in a drop of between a quarter and a half in NTD cases depending upon the initial NTD rate and the level of fortification. Two of the first countries to introduce mandatory flour fortification were the USA and Canada in 1998. I have used the Canadian experience as described by Philippe De Wals and colleagues to illustrate the effects of fortification. Flour and cornmeal fortification (150 µg/100g flour) began in Canada in 1997 and became mandatory at the end of 1998. Between 1996 and 2002 the rate of NTD almost halved from 1.69 to 0.86 cases per 1000 births (see figure 1). In the period, from 1997 when fortified products were gradually taking over, rates decline steadily then levelled out at 0.86/1000 in 2000. Before fortification there were much higher rates in some Canadian provinces than in others and fortification led to the biggest falls in those provinces (e.g. Newfoundland and Labrador) where initial rates were highest. Once fortification had been fully implemented there was little difference between rates in different provinces.
Flour in the USA has been fortified with 140 µg folic acid/100g flour and some other cereal products, including rice, must also be fortified. In 2007, Roy Pitkin reported that this had reduced NTD rates in the US by 25-30% which is about half the maximum reduction that could be achieved with optimal folic acid fortification. There has been consideration of whether the range or level of fortification in the USA should be increased.
Food fortification with folic acid is an effective way of reducing NTD rates.
Effectiveness of supplement recommendations
Despite strong recommendations in favour of fortification starting in 1992, the UK has delayed implementing these recommendations and in fact no European country has introduced mandatory fortification. In the UK, the initial recommendation was that women planning a pregnancy should take 400 µg/day of folic acid from before conception and during the first trimester. This advice has been extended so that virtually all women are advised to take this supplement routinely during their fertile years. In 2005, Lorenzo Botto and his colleagues looked at how recommendations to take folic acid supplements had affected the recorded rates of NTD in Israel and twelve European countries including the UK and Ireland. They could detect no significant change in incidence of NTD in the years after folic acid recommendations were made.
Morris and colleagues calculated rates of NTD in the UK over the period 1991-2012 (see figure 2). They found that rates did not change significantly in the period after mandatory fortification of flour started in the USA in 1998. Only around a quarter of UK women took supplements at the correct time and so current supplement advice is largely ineffective. They calculated that if the UK had introduced mandatory fortification in 1998 at the same level as the USA then in the period 1998-2012, there would have been 2014 less NTD-affected pregnancies and this figure is increasing by 150 each year. About half of all NTD affected pregnancies are spina bifida so without terminations there would have been 1000 extra severely disabled children born since 1998 and a further 75 additional cases added each year. Morris and her colleagues draw comparisons with the thalidomide example where the drug caused about 500 children in the UK to be born with disabilities. As already noted current low US fortification levels only prevents about half of the NTD cases that could be prevented by optimal folic acid fortification.
A number of factors contribute to the ineffectiveness of supplements. Few women routinely take the recommended supplements and up to half of pregnancies may not be specifically planned. As the development of the neural tube is largely complete at about one month after conception, supplements started after the woman knows she is pregnant are likely to ineffective or less effective. It is a general finding that people with the lowest intake of nutrients from food are the least likely to take supplements i.e. women most likely to benefit from folic acid supplements are the least likely to take them.
Recommending over the counter folic acid supplements is an ineffective strategy for preventing neural tube defects.
Barriers to fortification
Food fortification has a long history and has been effective in reducing the toll of some deficiency diseases such as endemic goitre and cretinism (iodine deficiency) and pellagra due to niacin (vitamin B3) deficiency. In the UK, it has been mandatory to fortify non-wholemeal flour with some B vitamins, calcium and iron since World War 2. Until recently, margarine had to be fortified with vitamins A and D. Many food manufacturers also choose to fortify products like breakfast cereals to enhance their healthy image.
Opposition to folic acid fortification ranges from specific concerns about safety to more philosophical arguments about whether fortification amounts to medication without consent and whether it is justified to treat many to help a few. Arguments such as these have greatly delayed the use of water fluoridation in this country despite overwhelming evidence that it would improve the dental health of children.
For every NTD pregnancy prevented, several hundred thousand people will receive the fortified food. In such circumstances, it is not unreasonable for governments to be cautious about whether and at what level to introduce compulsory folic acid fortification. At what point does justifiable caution become dithering? The US and Canadian governments waited about seven years after unequivocal evidence of efficacy before making fortification mandatory in 1998.
There have been objections to fortification because folic acid is not a form of the vitamin normally found in food i.e. it is a “foreign chemical”. Folic acid was for a time the only permitted form of the vitamin to be used in supplements and fortified foods within the EU and still only one other form is permitted. Unlike many natural folates, folic acid is relatively easy to produce and its potency is well-established. There have been suggestions that a derivative known as 5MTHF (5-methyl tetrahydrofolate) might be more acceptable because both natural folates and folic acid are converted to this form within the body. There have been no good clinical trials using this form of folate.
There have been three major safety concerns relating to the mandatory fortification of food with folic acid.
- Both folate deficiency and vitamin B12 deficiency lead to megaloblastic anaemia but untreated B12 deficiency also leads to severe neurological damage. High doses of folic acid can reduce the megaloblastic anaemia caused by B12 deficiency and so potentially delay diagnosis and treatment of B12 deficiency particularly in some elderly people. This delayed diagnosis and treatment might result in neurological damage. Cases of serious neurological damage caused by B12 deficiency are extremely rare (30 cases per year in the UK) and high doses of over 1000 µg/day are needed to mask the haematological consequences of B12 defiency. Recent survey data found that 7% of elderly men and 10% of elderly women had blood folate levels indicative of biochemical deficiency (note that 11% of women of childbearing age were also deficient). Average intakes of folate in the UK elderly are around 200 µg/day. This would thus seem like a theoretical rather than a practical hazard even amongst people who also take folic acid supplements.
- There were concerns that extra folate might reduce the effectiveness of some drugs like methotrexate that have an anti-folate action. Cancer cells are extremely rapidly dividing and their multiplication is slowed by these anti-folate drugs. Methotrexate is also frequently used in the management of rheumatoid arthritis. When methotrexate is used to treat rheumatoid arthritis, folic acid supplements reduce the side-effects of the drug without hindering its effectiveness.
- Epidemiological evidence shows that diets rich in folate are associated with reduced risk of bowel cancer. Nevertheless it was suggested that extra folic acid from supplements might increase bowel cancer risk by stimulating the development of benign bowel tumours into malignant ones. Stein Vollset and colleagues reported that rates of bowel cancer in the USA have declined steadily since 1970 and this fall was not arrested by the introduction of fortified breakfast cereals in 1973 nor the mandatory fortification of flour in 1998. Vollset and colleagues also amalgamated the results of clinical trials of folic acid supplements lasting up to 5.2 years and involving 50,000 subjects. They found that there was no change either way in the incidence of bowel cancer diagnosis when supplements were used for up to 5 years. Of course, it is still possible that any adverse events may develop many years later. However, if folic was advancing the development of existing benign tumours then one would expect to see effects within 5 years. In a cohort study of 100,000 Americans it was found that neither natural folate intake nor folic acid intake was significantly associated with any change in bowel cancer risk but that combined intake of all folates was associated with a small overall risk that was just statistically significant .
The above discussion suggests that none of the theoretical risks of folic acid fortification seem to produce actual harm in studies designed to test them. It is, however, very difficult to “prove” a negative especially to the satisfaction of those who may be philosophically opposed to “imposed medication”.
Where should we go from here?
My own personal view is that fortification of UK flour should now take place and I would personally suggest that we use a level around 50% higher than that currently used in the USA. This would maximise the number of NTD pregnancies prevented. To allow freedom of choice, unfortified flour could still be permitted provided it shows a warning that it does not comply with government recommendations on fortification. One could confidently expect this fortification to result in up to 300 fewer affected pregnancies each year. This would reduce the number of terminations, still births and severely disabled babies born. The consensus of available evidence suggests that this would be a safe as well as an effective measure. Fortification should also essentially eliminate folate deficiency in the UK although the practical benefits of this are difficult to quantify. There have been many claims made for benefits of folate supplementation including reduced heart disease, stroke and dementia risk but generally any evidence for such effects is currently weak or preliminary.
Another option is to take serious steps to increase the use of folic acid supplements amongst young women. There is a defensible case for this option given the concerns listed earlier. To have any chance of being effective this would have to be a substantial, well-funded and pro-active campaign including school and workplace promotional activities and delivery of free supplements to the “at risk” female population. Even with adequate resources my expectation would be that any benefits would be slow to manifest and much less than those achieved instantly by fortification.
The third and, in my opinion, unacceptable option is continued delay. Continued delay means that we are accepting the unnecessary birth of some severely disabled babies as well as over 200 preventable terminations of affected babies each year. The human and financial costs to affected individuals, families and society caused by the birth of severely disabled children is obvious. The long lasting traumatic effects of miscarriage, stillbirth or terminating a wanted baby are less obvious but nonetheless can be devastating let alone any financial costs.
The economic cost of fortification is very small in relation to the strictly economic costs of coping with the current level of NTD affected pregnancies. A cost benefit analysis suggests that in Australia the ongoing costs of fortification at the level I have advocated were around $1million per year but that savings resulting from the birth of fewer affected babies, fewer terminations and fewer stillbirths amounted to around $125 million.