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Folic acid

MRC research has resulted in 28.9 per cent of the world’s industrially milled wheat flour being fortified with folic acid, preventing thousands of cases of serious birth deformities and saving large sums of money in healthcare costs.

Neural tube defects (NTDs), which include conditions such as spina bifida, are among the most common severe congenital malformations. In the UK, there are just over one in 1,000 births with NTDs. This is one and a half times larger than the number in the US. The difference is believed to be because in the US it is mandatory to add folic acid to flour, a recommendation made originally on the basis of an MRC trial.

Vitamin suspects

Professor Richard Smithells, a British paediatrician, first suggested that vitamins may prevent neural tube defects1. He led a team that showed in a non-randomised controlled trial that a prenatal vitamin with 360 micrograms of folic acid taken several weeks before and during the early weeks of pregnancy was associated with a much lower rate of NTDs in babies. This raised two possibilities; that folic acid or another vitamin could prevent some cases of NTDs, or that women who chose to take the vitamins were a selected group with a better diet. The solution was to be found only by randomisation with a control group; in 1983, the MRC launched a trial.

The MRC study was a randomised double-blind prevention trial held at 33 centres. It aimed to determine whether supplementation with folic acid (a B vitamin) or a mixture of seven other vitamins (A, D, B1, B4, B6, C and nicotinamide), around the time of conception, could prevent NTDs. The trial involved 1,800 women at high risk because of a previous affected pregnancy, of whom nearly 1,200 had a completed pregnancy. The results, published in The Lancet in 19912, showed that folic acid had a 72 per cent protective effect and that the other vitamins had none.

Diet advice

The authors firmly advised that the diet of all women who may bear children contain adequate folic acid, especially women who had had an affected pregnancy. Within weeks of the publication of The Lancet article, the US Centers for Disease Control (CDC) recommended that women who had previously had an NTD pregnancy consume 4,000 micrograms of folic acid a day if planning a pregnancy. A year later, the CDC recommended that all women capable of pregnancy consume 400 micrograms of folic acid a day to prevent NTDs. Other countries followed with similar recommendations.

The most effective public health strategy to prevent NTDs is one that requires sufficient folic acid be added to a centrally-processed and widely-eaten food such as flour, rather than expecting that women will follow advice in taking daily vitamin supplements. In 1996, the US Food and Drug Administration (FDA) issued a regulation requiring all enriched grain products to be fortified with folic acid at a concentration of 140 micrograms per 100g. This resulted in a substantial improvement in blood plasma folate concentration3. Godfrey Oakley, Professor of Epidemiology at Rollins School of Public Health of Emery University, Atlanta, USA, said in correspondence with the MRC in 2006:

“The remarkable increase in plasma folate is like no other public health action that I know of.”

Many benefits

The increase in serum folate drastically reduces the birth prevalence of NTDs. In the US, Canada, Chile and Costa Rica, which all fortified flour between 1998 and 2000, the drop in NTD rates among live newborn babies was between 23 and 78 per cent4. All countries that introduced mandatory fortification of flour with folic acid consistently reported similar significant decreases in NTD-affected live births.

Folic acid also decreases blood levels of the amino acid homocysteine, an independent risk factor for cardiovascular disease. This may reduce the risk of heart disease and strokes5. This year, in a study of newborn infants born between 1996 to 2001, Norwegian researchers showed that folic acid supplementation reduces the risk of facial clefts (a harelip) by about a third6.

Fortification is cost-effective. Once the fortification infrastructure is in place, the cost of adding it to enriched flour is less than £0.01 per kilogramme of flour4. The ratio of direct cost of care of NTD to fortification in the US is 40 to one. In Chile, it is at least 10 to one.

Ten per cent of all the flour produced in the world is now fortified with folic acid. The UK’s Food Standards Agency (FSA) has just recommended that folic acid be added to flour or bread, and is due to approach the Government with its advice. This decision has been delayed due to a concern that folic acid fortification may harm people with undiagnosed vitamin B12 deficiency. This is because folic acid may eliminate the anaemia, which indicates B12 deficiency, but not the damage to the nerves, spinal cord or brain that lack of B12 causes7. However, there is little evidence to support this hypothesis.

Folic acid: research and public policy

  • 1968: Hibbard and Smithells link folate deficiency in pregnancy with NTDs.
  • 1991: an MRC-funded randomised, controlled trial shows that folic acid supplements protect women with a prior pregnancy affected by spina bifida or anencephaly (NTDs) from recurrence. The study is halted so all subjects can receive folic acid supplements. Study results are published in The Lancet.
  • 1991: the US Centers for Disease Control and Prevention (CDC) advises that women with previous pregnancies affected by neural tube defects consume 4,000 microgrammes of supplemental folic acid daily. The FDA opposes the recommendation.
  • 1992: a Hungarian randomised, controlled trial of folic acid supplementation for all women in a general population shows that folic acid supplements prevent NTDs, cutting their numbers by half.
  • 1992: the US Public Health Service recommends all women who could get pregnant to consume 400 microgrammes of folic acid a day.
  • 1996: in a volte-face, the FDA publishes new fortification regulations requiring that folic acid be added to enriched grains at a concentration estimated to increase synthetic folic acid consumption by 100 microgrammes.
  • 1998-2000: fortification in place in Canada, Chile and Costa Rica; drop in NTD cases in these countries and US is between 23 and 78 per cent.
  • 2000: the UK Department of Health Committee on Medical Aspects of Food and Nutrition Policy publishes report on ‘Folic acid and the prevention of disease’, concluding that universal fortification of flour with folic acid would significantly reduce the number of conceptions and births affected by NTDs.
  • 2002: the UK Food Standards Agency (FSA) Board first discusses the possibility of folic acid fortification. The Scientific Advisory Committee on Nutrition (SACN), an independent group of scientific experts who advise the Government, starts reviewing the risks and the benefits.
  • 2004: UK Health Ministers call for a consideration of the wider impact of folic acid fortification. They decide not to introduce mandatory fortification, due to outstanding concerns about vitamin B12-deficiency.
  • 2006: the SACN requests extra time to review scientific evidence and delays the start of a UK consultation to seek views of consumers, stakeholders and industry.
  • End of 2006: SACN recommends the implementation of mandatory fortification and the FSA launches a three-month long public consultation on the proposal to fortify flour with folic acid before ministers make a final decision in May 2007.
  • May 2007 FSA recommends folic acid be added to flour or bread.

References

1. Hibbard & Smithells (1968). Folic acid metabolism and human embryopathy. The Lancet, i, 1254.

2. MRC Vitamin Study Research Group (1991). Prevention of neural tube defects: results of the Medical Research Council Vitamin Study (1991). The Lancet, 338, 131.

3. Jacques et al. (1999). The effect of folic acid fortification on plasma folate and total homocysteine concentrations. NEJM, 340, 1449.

4. Grosse et al. (2006). Folic acid fortification and birth defects prevention: lessons from the Americas. AgroFOOD industry hi-tech, 17, 50.

5. Yang et al. (2006). Improvement in stroke mortality in Canada and the United States, 1990 to 2002. Circulation, 113, 1335.

6. Wilcox et al. (2007). Folic acid supplements and risk of facial clefts: national population based case-control study, BMJ, DOI:10.1136/bmj.39079.618287.OB.

7. SACN report on folate and disease prevention, 2006.

MRC, January 2007, updated May 2007, minor update September 2013

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