Primary Prevention of Neural Tube Defects with Folic Acid

What is the evidence that NTDs are preventable?

Without a doubt, good nutrition through a diet containing abundant fresh fruits and vegetables along with a well-balanced intake of other representative food groups goes a long way towards preventing NTDs. In all geographic regions during periods of drought, famine and war, the rate of NTDs strikingly increases, and during periods of prosperity it declines. ^18 32

Intervention studies evaluating the impact of micronutrients, in particular folic acid, have been done using folic acid with or without other vitamins and minerals. The evidence is clear that periconceptional use of supplements containing folic acid substantially reduces the risk of occurrence (first affected pregnancy) and recurrence (additional affected pregnancies) of NTDs. Table 1 summarizes the results of cohort and case control studies, randomized and nonrandomized trials and a community-based public health campaign. From these studies it is estimated that at least half the cases of NTDs may be prevented if women consume sufficient amounts of folic acid before conception and during early pregnancy. There is some evidence to suggest that periconceptional use of supplements containing folic acid is also effective in reducing the risk of other common congenital anomalies of multifactorial etiology. These anomalies result from incomplete development and/ or failure of fusion of migrating cell masses. Folic acid may reduce the risk of congenital heart anomalies, in particular conotruncal heart defects, ^{33 35} some types of limb anomalies, ^33 34 obstructive urinary tract anomalies, ³³,³⁶ pyloric stenosis ³³ and orofacial clefts. ^{33 34 37 38}

How does folic acid work?

The specific action of folic acid in affecting the pathogenesis of NTDs is largely unknown. ³⁵ Folic acid is essential for the synthesis of nucleic acids and amino acids and for cell division. In this capacity, it would be anticipated that not only NTDs but also other isolated structural anomalies due to incomplete development would be influenced by the availability of folic acid during embryogenesis.

Folic acid may have other health benefits as well. Folic acid supplementation is effective in reducing high blood homocysteine levels, which are associated with increased risk of coronary heart disease. ³⁹ Also, poor folate status has been associated with an increased risk of cancer, particularly colorectal cancer. ⁴⁰

To be effective in preventing NTDs, when should folic acid be taken?

Abundant folic acid needs to be available in early gestation while the neural tube is closing - i. e., from 21 to 28 days after conception, or the 6th week after the beginning of the last menstrual period. It is recommended that daily folic acid supplementation be started at least 2 to 3 months before conception and continued throughout the first trimester of pregnancy. However, many pregnancies are unplanned. For women who are not intending to get pregnant but nevertheless could become pregnant, daily folic acid supplementation on an ongoing basis would be advisable.

For maternal nutritional needs, folic acid needs to be continued throughout the remaining months of pregnancy, as well as during lactation.

What type of supplement can I recommend to women who could become pregnant?

The available evidence best supports a recommendation for a multivitamin-multimineral supplement containing folic acid at 0.4 mg per daily dose to reduce the risk of first occurrence of an NTD.

Over-the-counter vitamin and mineral supplements, however, are available in a great variety of combinations of nutrients at a wide range of levels. None of these supplements is designed specifically for use in the periconceptional period. At this time, there are no guidelines that define the appropriate composition of multivitamin-multimineral supplements for this use. While recommended daily intakes and tolerable upper levels (ULs) of daily intake have been determined for some nutrients and, in some cases, for nutrient intakes by pregnant women, ULs have not been established specifically for the periconceptional period.

A few guidelines can be offered to help in the choice and use of a supplement:

• Choose a multivitamin-multimineral supplement that contains 0.4 mg folic acid in a daily dose.
• There is no need to choose a product labelled "For therapeutic use only". These supplements usually provide nutrients at a higher dose than is necessary and may be more expensive. They may contain trace minerals such as molybdenum, selenium and chromium, but there is very little likelihood that a woman will be deficient in these nutrients and require a supplement.
• To be prudent, avoid supplements containing herbs and various other extraneous "non-medicinal ingredients".
• Try to select a product containing vitamin A as beta-carotene rather than as retinol. High doses of vitamin A as retinol cause several types of birth defects in animals, including neural tube defects, and have caused birth defects in humans. ⁴¹ Although the exact dose above which vitamin A can cause harm to the fetus is unknown, supplements sold without a prescription may not contain more than 10,000 IU (3,330 RE) of vitamin A per table 1, ⁹ which is also the upper limit of supplementation with retinol recommended by the Teratology Society. ⁴¹ Many supplements include at least a portion of the vitamin A in the form of beta-carotene, which is not believed to have teratogenic effects. ⁴¹
• Women should not take more than one daily dose as indicated on the product label. If a woman misses taking a tablet on 1 or more days, she should not try to "catch up" by taking the missed pills all at one time. Excessive amounts of some nutrients, including vitamin A as retinol, may be harmful, particularly to an embryo in the very early stages of development.

What about food fortification? Why should women still take supplements containing folic acid?

In Canada since 1998, white flour and enriched pasta and cornmeal have been fortified with folic acid on a mandatory basis as a public health strategy to improve dietary folate intakes, with the expectation that the rate of NTDs might be reduced. White flour is fortified with folic acid to a level of 0.15 mg per 100 g of flour. This is a little more than twice the level of naturally occurring folate* found in the whole grain. Enriched pasta is fortified with folic acid to 0.20 mg per 100 g. A serving of cooked, enriched pasta contains about 0.125 mg of folic acid (some of the added folic acid is lost in the cooking water) and two slices of white bread contain 0.06 mg.

The amount of folic acid added to flour and the other cereal products was kept low because of concerns that higher amounts would create a risk for individuals with undiagnosed vitamin B12 deficiency. The prevalence of low vitamin B12 status has been found to be relatively high, especially among people over 50 years of age. ⁴²

Overall, fortification is estimated to increase the daily intake of folic acid among women 18-34 years of age by approximately 0.1 mg. Since the average daily diet of women of reproductive age contains approximately 0.2 mg of folate, fortification increases the average intake of this nutrient by approximately 50%. Although this is a substantial increase, it does not result in the intakes achieved in the studies cited above. Nevertheless, the ultimate benefit of fortification in reducing the risk of NTDs is yet to be determined, since the minimum effective dose of folic acid is not known.

Many of my patients have healthy diets. Do they need to take supplements?

Even allowing for food fortification with folic acid, it would be difficult for most women to consume enough folic acid from diet alone to achieve a daily intake equivalent to a 0.4 mg supplement on top of diet. All women should be encouraged to eat a healthy diet, according to Canada's Food Guide to Healthy Eating, ¹⁰and those who could become pregnant should also take a daily supplement containing folic acid.

Appendix I, which lists dietary sources of folate, will help women choose the foods from the various food groups that are higher in folate. Folate is found in nearly all foods, but levels vary considerably. Folate is susceptible to destruction by excessive or prolonged heating, so overcooked foods may be low in folate.

Some of my patients may not be able to afford supplements. What can I do?

Women who indicate that they cannot afford vitamin supplements may also have poor diets and possibly other risk factors for adverse pregnancy outcomes. Health professionals can help women who may not be able to afford supplements by referring them to local programs and services that support economically disadvantaged women and their families. An example is the Canada Prenatal Nutrition Program. These issues are discussed in more depth in Nutrition for a Healthy Pregnancy: National Guidelines for the Childbearing Years, ⁹ and Family-Centred Maternity and Newborn Care: National Guidelines. ⁴³

* The forms of folate that are present naturally in foods are polyglutamate forms. They have a lower bioavailability (rate of absorption from the intestine) than synthetic folic acid. ¹¹

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