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Motherisk Update 2014
Fetal Alcohol Canadian Expertise (FACE) Satellite Meeting,
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Taking Folic Acid Before You Get Pregnant: Periconceptional Folate Preventing Neural Tube Defects
Periconceptional Folate Preventing Neural Tube Defects
Neural tube defects (NTD) affect about 0.6/1000 born babies in Canada. Comprised mainly of anencephaly and meningomyelocele, NTD are serious lethal or severely debilitating congenital malformations. The risk of a recurrence of NTD in a woman who has had a previous NTD is about 3-4%. During the last decade effective antenatal methods have been developed to diagnose NTD in utero, with second trimester ultrasound combined with amniotic or maternal blood alfa-fetoprotein offering an almost 100% sensitivity in some centers. However, the above tests are not performed routinely on women with unknown previous risk for NTD (such as previous NTD or those receiving valproic acid, carbamazepine or retinoids).
During the last 2 decades evidence has been accumulated suggesting that low preconceptional consumption of folate and vitamins is associated with an increased risk of NTD. Being retrospective, these studies could not separate between the potential effects of other vitamins vs folate. The main criticism against these observational studies was that women consuming low amounts of folate and vitamins may have clustering of many other nutritional and socioeconomic risk factors leading them to increased teratogenic risk. However, this controversy was layed to rest when the British Medical Research Council study, a multinational, double blind placebo control effort, has clearly proven the protective effect of pharmacological folate dose (4 mg/d) over placebo on the recurrence rate of NTD in women who had a previous NTD. Vitamins themselves (without folate) had no protective effect.
It was subsequently argued, that this protective effect may not be relevant to the prevention of the occurrence of a first NTD in the general population. However, a recently completed double blind, placebo control study from Hungary has clearly shown the protective effect of folate at 0.8 mg/d plus vitamins over placebo in women with no previous history of NTD. At present, no study has examined the efficacy of a lower dose of folic acid, such as 0.4 or 0.2 mg/d. It is probable that in a heterogenous society such as in Canada, different ethnic groups have different magnitude of risks for NTD; however, this new evidence suggest that, at least in part, NTDs are caused by folate deficiency. An association between folate deficiency and other malformations (e.g. cleft lip palate) has been suggested, but at the present time has not yet been verified.
In Canada, the recommended dose of dietary folate for the general population was reduced almost two decades ago from 0.4 to 0.2 mg/d. This recommendation stemmed from the concept that 0.2 mg/d is satisfactorily high to saturate hepatic stores of folate. With the new data presented above it is quite clear that this level of folate may increase the risk of NTD in Canada. Indeed, Health & Welfare has recently increased its recommendations in parallel to similar changes in the US.
There is recent evidence that large segments of North American women below or near poverty have median intakes of folic acid of 0.15 mg/d. Even among those above poverty, many have very low folate intake. At present it is not clear whether 0.4 mg/d of folate is inferior to the 0.8 mg/d tested in Hungary; however, it is probable that intake of 0.2 mg/d is below the preventive dose. In its recent guidelines, Health & Welfare recommends daily consumption of 0.4 mg folic acid by inferring from observational studies, and despite of the fact that the two recent intervention studies used 0.8 or 4 mg folate.
Because NTD are induced in the first 28 days of pregnancy, adequate maternal folate intake has to start preconceptionally. However, with half of all pregnancies in North America being unplanned, it is evident that recommendations by themselves are not likely to reach many women, and are very likely to miss high risk, low socioeconomic class women who tend to consume substantially less folate. A variety of methods have been suggested to supplement women of reproductive age with adequate folate. While educating women to consume more fruits and vegetables may achieve that goal, supplementation of basic food sources such as bread, salt, cereals or milk may not be dependent on changing behavior patterns of women. The potential deleterious effects of incorporating folic acid in basic food supplementation have to be carefully reviewed. Some masking of B12 deficiency may occur in patients with combined deficiencies of vitamin B12 and folic acid.
Folate-deficiency-induced NTD are now proven to be prevented at the primary level (rather than secondary prevention by pregnancy termination). This is an exciting opportunity, similar in magnitude to iodine preventing cretinism. The Canadian health community, in concert with the various governments should address these issues as soon as possible. Any delay in response will result in unnecessary occurrence of NTD with immense suffering and cost to the children, their families and to the Canadian public at large.