Folic acid

Optimal dose of folic acid supplementation

For almost 20 years, the recommended daily dose of folate supplementation has been 0.4 mg/d. In fact, prenatal multivitamins invariably contain 0.8 to 1.1 mg of folic acid, and this had led to the assumption that daily supplementation with this dose is sufficient to prevent NTDs. However, in 2001, Wald et al systematically reviewed all reports of the correlation between ingested dose of folate and resultant serum concentrations.6 Using the data by Daly et al,5 who correlated maternal serum folate levels with the risk of NTDs, Wald et al concluded that the current recommended daily dose of folate will render only partial protection against NTDs. According to Wald et al’s analysis, 5 mg/d of folate would be necessary to render 90% protection within the populations.6 Their analysis has been recently corroborated by our findings that in 2005 and 2006, 40% of women in Ontario did not achieve the protective 900 nmol/L red blood cell folate, despite flour fortification and the fact that more than half of pregnant women supplemented with prenatal multivitamins.7

Potential risks

Before recommending prenatal supplementation with higher doses of folic acid, one needs to consider potential health risks of such an increase.

It has been proposed that higher levels of folate can mask pernicious anemia due to B12 deficiency. Similar concerns surrounded the original North American flour folate fortification program in 1998, but were not shown following the fortification. Several recent studies have failed to show such risks.8 A recent US study suggested an association between high folate levels in older Americans and a risk of cognitive impairment.9 However, cognitive impairment is not a component of pernicious anemia, and in that study there was no increased risk for neuritis, which is a typical finding of pernicious anemia. One has to remember that the risk for the pernicious anemia is different if the whole population consumes flour with higher levels of folate, as opposed to giving 5 mg/d to pregnant women for a limited time. In fact, direct measurements of B12, or higher supplementation of B12, can further allay these concerns.

If women do not comply with the recommendation to take the currently available folate-cotaining preparations, it is reasonable to question whether or not they would take the preparations containing 5 mg of folate daily. In a recent controlled trial of prenatal vitamin supplements for women who discontinued or had not started using prenatal vitamins, their compliance with 2 different brands of prenatal vitamins averaged 58% and ranged from 0 to 100%, despite the participation of self-selected, motivated women.10 Pharmacologically, administration of 5 mg of folate daily in women who have a lower compliance with taking medication should provide many more women with protective levels of folate.

Although laboratory studies have suggested that folic acid might increase the risk of certain cancers, population-based studies have repeatedly shown folic acid use to be associated with a 20% to 30% decline in incidence (Table 18). Scientists therefore refer to the potential dual effects of folate on cancer risk, with increased risk for individuals with a history of or predisposition to cancer.11 There is no question that an increased risk of cancer associated with folate use, even if it exists, is a result of long-term exposure to folate over many years, and not to several months of dosing during pregnancy.

Incidentally, a systematic review that assessed the association between folate status and twinning found possible but non-significant evidence of periconceptional folate intake and twinning.8

Conclusion

Unless prescribing clinicians can ensure that pregnant women will be appropriately compliant in using pre-natal vitamin supplements containing 0.8 to 1.1 mg of folate, they should consider prenatal vitamin supplements containing 5 mg of folate daily.12 Five mg of folate should be used several months before conception until the end of the first trimester of pregnancy.