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Alcohol and Substance

Folic acid and neural tube defects: Good news at last!

Gideon Koren, MD, FACCT, FRCPC

November, 1999



I read last year that Canada has followed the United States in fortifying flour with folic acid to prevent neural tube defects. Do we know yet whether this strategy is working?


In Canada, flour is fortified with folic acid to a level of 0.15mg/100g. Although a mandatory date was set for November 1, 1998, most if not all companies implemented the change on or before January 1, 1998. Recent figures from the United States, where the deadline for fortification was January 1998, show that by March 1999, mean folate levels in flour doubled, substantially decreasing the risk for neural tube defects.

Two large randomized, blinded controlled studies have documented the effect of folic acid supplementation before pregnancy on prevention of neural tube defects (NTDs).1,2 On average, Canadian women consume 200mg/d of folic acid; 400 mg/d are needed to prevent a first NTD.3 Because the neural tube is fused within the first month of pregnancy, folic acid supplementation later than that (eg, at 2 or 3 monthsí gestation) does not prevent NTDs. Because at least half of all pregnancies are unplanned, many women are likely to find out they have conceived too late for an intervention with folic acid to have a therapeutic effect. Because of this, the only effective solution to preventing folic-acid preventable NTDs is to fortify a commonly used food staple.

In January 1998, the United States Food and Drug Administration put into effect a new regulation that enforced adding 140mg of folic acid per 100g of flour (in addition to other vitamins already added). This level of fortification would, it was believed, increase "average" womenís folic acid intake by 80 to 100mg/d. Researchers acknowledged that this level might not be high enough to prevent all preventable cases of NTDs.4 In May 1999, Jacques and colleagues5 reported the effect of this fortification, as measured in March 1999, using patients followed in the Framingham Heart Study.

Among subjects not using vitamin supplements, serum concentrations of folic acid increased from 4.6 to 10.0ng/mL (11 to 23nmol/L) (P<.001) between prefortification and postfortification visits. The prevalence of low folate concentrations (<3ng/mL) decreased from 22% to 1.7% (P<.001).

To put this important result in the context of risk for NTDs, we reviewed the concentration-response curve of serum folate with NTD risk per 1000 births established by Daly et al.6 Based on this curve, the risk of NTDs would have decreased from 2 to 0.9 cases per 1000 births (Figure 15,6). In Canada, this would mean a reduction from 800 cases to 360 cases a year, although we should be cautious in extrapolating Irish figures to those in North America because North Americaís population is more heterogenous in terms of racial origins.

We must await new statistics on changes in serum folate concentrations in Canada after fortification. It is conceivable that a 30% to 40% decrease in NTDs could be expected even with the relatively low level of fortification.


  1. Wald N, Sneddon J, Densem J, Frost C, Stone R. MRC vitamin Study Research Group. Prevention of neural tube defects: results of the MRC Vitamin Study. Lancet 1991;338:131-7.
  2. Czeizel AE, Dudas I. Prevention of the first occurrence of neural tube defects by periconceptional vitamin supplementation. N Engl J Med 1992;327:1832-5.
  3. O'Connor DL. The folate status of Canadian women. In: Koren G, editor. Folic acid for the prevention of neural tube defects. Toronto, Ont: The Motherisk Program; 1995. p. 73-87.
  4. Oakley GP Jr. Eat right and take a multivitamin. N Engl J Med 1998;338:1060-1.
  5. Jacques PF, Selhub J, Bostom AG, Wilson PWF, Rosenberg IH. The effect of folic acid fortification on plasma folate and total homocysteine concentrations. N Engl J Med 1999;340:1449-54.
  6. Daly LE, Kirke PN, Molloy A, Weir DG, Scott JM. Folate levels and neural tube defects: implications for prevention. JAMA 1995;274:1698-702.

Figure 1. Relationship between serum folate level and risk of neural tube defects (NTDs): The increase in folate levels in the United States decreased the risk of NTDs by more than half.

Adapted from Daly et al6 with additional data from Jacques et al.5

© Canadian Family Physician 1999;45:2605-2606.
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