Folic acid

The most compelling evidence supporting the benefits of supplementation in pregnancy is linked to the role of folate.

The extent to which various forms of folate can be absorbed varies and, on average, only about half of the folate in the diet is available. Rich sources of food folates include broccoli, spring greens, cabbage, cauliflower, iceberg lettuce, parsnips and oranges. Other sources of folate include liver, yeast, yeast extract and fortified cereals. Extensive losses of food folates of 50-80% can occur during cooking and food preparation.

The form of folate in supplements and fortified cereals is folic acid. Unlike food folates, this synthetic form is much more stable and has been shown to be 1.7 times more available than food folates1.

Role of folate in preventing neural tube defects

Folate is well known to play a critical role in cell division and is crucial in foetal development. In 1983, the British Medical Council2 undertook a definitive study of women who had had a first occurrence of a NTD. The study, a large randomised double blind design, examined the effects of supplementation with additional folic acid and other vitamins on the incidence of a second NTD. The results demonstrated that a 4mg supplement of folic acid could reduce the recurrence of NTDs by 72% in women already affected by a previous NTD birth. No statistically significant effect was seen from the vitamin only (minus folic acid) arm of the trial on the incidence of NTD.

Three other randomised intervention trials have been conducted3,4,5 with folate levels ranging from 0.36mg to 4mg with similar results. Significantly, one of these studies5 also looked at the effect of a multivitamin supplement including folic acid at 0.8mg (800mcg) on the incidence of first occurrences of NTDs. Of 4156 pregnancies, there were no occurrences of NTD in the vitamin supplemented group and no re-occurrences of NTDs in the 38 pregnancies with previous NTDs that received the vitamin supplementation.

Back to top

Recommendations and food fortification

In its report in 2000, the Committee on Medical Aspects of Food Policy (COMA)1 endorsed previous recommendations that all women who could become pregnant should continue to be advised to take 400mcgs per day as a supplement prior to conception, and until the twelfth week of pregnancy. They estimated that 400mcgs of folic acid from supplements together with 200mcgs from the diet would be expected to reduce the current annual level of NTD births (600-1200 per year) by about half. The report also endorsed previous advice that women with a previous pregnancy affected by NTD, who wish to conceive, should be advised to take a daily supplement of 5mg of folic acid.

COMA1 also considered the question of mandatory fortification of flour and flour products with folic acid as a public health measure and made recommendation for fortification at 240mcg/100g. Further consideration of this proposal is ongoing by the Food Standards Agency (FSA). In particular the FSA wishes to ensure that suitable surveillance can be put in place to ensure that B12 deficiency, which can be masked by high intakes of folic acid, is not overlooked in older people. No other subgroup of the population is thought to be at risk.

In Canada6 and the USA7 flour and pasta have been fortified with folic acid since 1998. Women who could become pregnant are still advised to take a supplement of folic acid of 400mcgs per day. Since introduction, rates of NTD in some Canadian provinces and the USA have declined significantly.

Back to top

Can folate prevent other congenital abnormalities?

A number of studies have reported a protective effect from folic acid given preconceptually8,9,10,12 in the prevention of defects of the face although one study failed to demonstrate this12. Czeizel11 concluded that the effect was likely to be dose dependant and might not be prevented by the normal level of preconceptual daily folic acid supplementation. He recommended a daily dose of 6mg during the critical period of development of these defects to prevent second occurrences. Shaw10 concluded that his own results might be partly attributable to other components of the multivitamin supplement used.


Researchers Subjects
Tolarova8,9 Dramatic reduction in re-occurrences of cleft abnormalities (64%) with high dose folic acid (10mg)
Shaw10 Multivitamins containing 0.4mg or more of folic acid, reduced the occurrence of cleft lip and palate by 27-50%
Czeizel11 No reduction in incidence of orofacial cleft with 0.8 mg folic acid. Reduction of clefts seen after the use of high doses of folic acid (3-9mg/d) in the early post conception period
Hayes12 No protective association between periconceptional folic acid supplementation and the risk of oral cleft

Back to top

Other areas of interest

During pregnancy, low dietary and circulating levels of folate are associated with increased risks of preterm delivery, low birth weight and growth retardation13. Folate deficiency is also associated with an increase in spontaneous abortions. The incidence of NTD amongst spontaneously aborted foetuses is 10 times higher than the rate at birth14. Two studies15,16 set out to find an effect of supplemental folate on miscarriage rates. Neither study found an effect although George15 did find that low folate status was associated with an increased risk of early spontaneous abortion. Raised homocysteine, (a marker for poor folate status) has been shown to be a possible risk factor in 21% of unexplained recurrent early miscarriages17 and for placental abruption or infarction18.

James19 suggested that abnormal folate metabolism, in part caused by a gene mutation, could be a risk factor for Downs Syndrome. In a case controlled study, Czeizel20 compared 781 subjects with Downs Syndrome (DS) with matched controls for an effect of multivitamin supplements on the incidence of DS. A significant protective effect was seen with large doses of folic acid (6mg) and iron (150-300mg/d of ferrous sulphate) during the first gestational month.

In summary, folate is critically important for foetal development. It acts as a co-factor for many essential reactions including those involving amino acids (the building blocks for protein) and is required for cell division and DNA synthesis. Folate deficiency can occur as a result of dietary inadequacy or because metabolic requirements are increased by genetic defects. Poor dietary folate intake is a significant risk factor for a number of adverse birth outcomes including increased risk of NTDs, preterm delivery, low birth weight and foetal growth retardation. High concentrations of homocysteine, an indicator of poor folate status, have been associated with increased spontaneous abortion, and other serious complications of pregnancy13.

Back to top

References

  1. COMA RHSS 50 2000; DoH HMSO
  2. MRC Lancet 1991; 388: 131-7
  3. Lawrence KM et al. BMJ 1981; 282:1509-1511
  4. Kirke PN et al. Arch Dis Child 1992; 67: 1442-1446
  5. Czeizel AE et al. New Eng J of Med 1992; 327: 1832 1835
  6. Abbe MRL et al. Proceedings of the Nutrition Society 2003; 62: 413-420
  7. CDC: MMWR Morb Mortal Wkly Rep 2004 May 7; 53 (17): 362-365
  8. Tolarova M. Lancet 1982 ii 217
  9. Tolarova M et al. Teratology 1995; 51: 71-78
  10. Shaw GM et al. Lancet 1995 Aug 12; 346(8972): 393-6
  11. Czeizel AE et al Teratology 1996; 53: 345-351
  12. Hayes C et al. Amer J Epidem 1996; 143: 1229-1234
  13. Scholl TO, Johnson WG Am J Clin Nutr 2000;71:1285S-303S
  14. Bryne J Warburton D Am J Med Genet 1986;25:327-33
  15. George L et al. JAMA 2002; 288: 1867-1873
  16. Gindler J et al. Lancet 2001; 358: 796-800
  17. Wouters MGAJ et al. Fertil Steril 1993; 60:820-825
  18. Goddijn-Wessel TAW et al. Eur J Obstet Gynaecol Reprod Biol 1996; 66 23-29
  19. James SJ et al. Amer J Clin Nutr 1999; 70:495-501
  20. Czeizel AE et al. Nutrition 2005; 21(6): 698-704
 
Not a midwife or healthcare professional?
Click here