Scientific Explanation of Folic Acid Prevention

Eat Your Vegetables and Take Your Vitamins ... To Prevent Birth Defects!

Mark J. Merkens, M.D.
Director, Oregon Spina Bifida Program
Originally published in The Doernbecher Journal Vol. 2 (1), Spring 1996. p4-6.

Funded in part through NEXT STEPS: The Oregon Spina Bifida Project: building a community-based health delivery system for children with special health care needs. Grant # MCHJ-415087, Maternal and Child Health Bureau.

The Oregon Spina Bifida Program serves 350 children affected by a family of congenital conditions formally known as Neural Tube Defects (NTD's). Recent research illuminates simple steps to prevent these complex conditions which may eventually put this program out of business. We couldn't be happier.

These complex conditions permanently affect numerous organ systems. The congenital defect results from failure of closure ("neurulation") of the embryologic nervous system very early in pregnancy at 23 to 30 days gestation. The resulting deformity ranges from a small opening in the spinal cord at the sacral region, to an open skull or even absent brain. The latter is known as anencephaly and is not compatible with life. The open deformity of the spine is technically called myelomeningocele and causes a complexion of problems similar to a permanent spinal cord injury; everything below is affected.

Currently about 2,500 children are born in the United States each year with NTD's ⁽¹⁾; twenty five of these come from Oregon. Many suffer a life long disability and require multiple surgeries and complicated equipment. A few suffer a lifetime of discomfort. The cost of care averages $50,000 in the first year of life, $12,000 yearly thereafter, and $250,000 in a patient lifetime ⁽²⁾.

It is not known how frequently these abnormal formations occur.

The mechanism for this deficient formation of the nervous system so early in pregnancy is multifactorial. Differing ethnic rates, regional variations, family clustering, and increased risk of recurrence in later pregnancies all suggest genetic mechanisms. But environmental associations have long been observed. Birth rates vary with time and location, and there are temporal clusters particularly following famine and poverty. Frequency also varies with socio-economic status. These defects are also more common when, during pregnancy, the mother takes certain medications (Valproate for seizures), has diabetes, or drinks heavily with resulting Fetal Alcohol Syndrome (FAS).

Years ago it was proposed that there might be a mechanism which could explain these apparently disparate observations and characteristics. A dietary factor during pregnancy could impact metabolism in a targeted way, affecting the normal migration of neural crest cells trying to form the fetal nervous system. Perhaps one metabolic pathway may be side tracked by various deleterious effects. A genetic variation in a metabolic pathway would explain ethnic, regional, familial, and temporal variations. A single pathway might combine potential environmental as well as genetic patterns in the occurrence of spina bifida and other Neural Tube Defects. The dietary factor has been found to be one of the B vitamins, folate.

In the late nineteen-fifties it was shown that a chemical called aminopterin which blocks folate, causes NTD's in laboratory animals when they were also deficient in folate in their diet. Twenty years later a British researcher found low levels of folate in the serum, especially in the red cells, of mothers who had borne a pregnancy with NTD. ^(3.)

In the last ten years there have been numerous clinical investigations of the impact of dietary folate during pregnancy. Early retrospective studies surveyed mothers to report on vitamin usage during previous pregnancies. History of ingestion could be compared between groups of mothers of children with NTD's and those without. Four out of five major studies confirmed a 50 to 80% decline in these birth defects if mothers had taken supplemental folate early in pregnancy, or better still, prior to conception. ^(4.)

Such retrospective clinical surveys are flawed by recall. Controlled prospective clinical trials with supplemental folate were finally run in the late '80's and early nineteen-nineties. The British, who have a much higher prevalence than in the U.S.A., ran a multicenter study in seven countries, treating mothers who had already borne a child with an NTD. They prescribed 4 mg of folic acid (the synthetic form of folate), ten times the recommended dietary allowance (RDA). The study was halted early when the statistics revealed a 72% lower chance of bearing another pregnancy with an NTD in the supplemented mothers. ^(5.)

The definitive study was finally reported in late 1992. A Hungarian group conducted a randomized, controlled trial of periconceptional multivitamin supplementation, including low dose folate. ^(6.) The supplemented mothers had no affected fetuses in 2,000 pregnancies, while those 2,000 pregnancies supplemented only with trace elements bore six infants with NTD's. And, the treated mothers had newborns with lower rates of all forms of birth defects!

The presumed mechanism of folate is as a substrate in DNA synthesis. Deficiency causes an increase in levels of homocysteine. It is not known how that affects neurulation, but we now know the causative step in the metabolic pathway.

Enter the world of molecular biology. The deranged metabolic pathway is described in simultaneous reports of findings of an abnormally slow enzyme in the DNA synthesis pathways at the site of function of folate in 15% of children with spina bifida, as well as in their mothers and/or their fathers. ^(7.)"In some pregnancies, there was an increased requirement for folate to ensure normal closure of the neural tube." Some women unknowingly have a need for greater folate intake than the current Recommended Daily Allowances (RDA's). We have thus tied together our understanding of the environmental, dietary, and genetic aspects of neural tube defects.

That slow enzyme had already been known. It is a common genetic variant of methyltetrahydroxy folate reductase (MTHFR), markers of which are found in up to half of the American public. ^(8.) The homozygous state of the abnormal enzyme in folate metabolism had already been associated with elevated levels of homocysteine and well documented increased risk of cardiovascular disease. ^(9.)

Reference 8. 5,10 Methylenetetrahydrofolate reductase and other enzymes important in homocysteine metabolism.

 

Where do we get folate to prevent birth defects and lower rates of cardiovascular disease? The Greek origin of the word folate means "leafy green". Your mother was right: eat your green vegetables ! There is no known toxicity. Americans tend to get their folate from these food items, in order of frequency---orange juice, wheat products, beans, salad, non-fortified cereal, eggs, and liver. But only twenty percent of women of child bearing age get adequate folate in their natural diet to adequately bathe their ovaries to prevent NTD's. It is presumed that the same dietary unmet needs occur in the segment of the general population who would have lower rates of cardiovascular disease if their enzyme needs were covered.

This information, with a few additional facts, can be used to generate public recommendations. In the U.S., half of all pregnancies are unplanned. Over 90% of NTD's are first sporadic occurrences. Strategies directed at recurrence to the same mother are therefore insufficient. Strategies directed at the diagnosis of pregnancy are too late; the embryologic defect has already occurred. Dietary change is a long term goal. With these facts in mind, a more inclusive policy recommendation has been devised. The Centers for Disease Control therefore recommend that every woman, "capable of becoming pregnant" (euphemism for having sex) should supplement her diet with 400 micrograms or 0.4 mg folic acid (the synthetic form of folate) daily throughout her child bearing years. ^(4.) That recommendation is easy to carry out because the folic acid content of many non-prescription daily vitamins is just that--0.4 mg or 400 micrograms.

Women who have already had a pregnancy with an NTD are at risk for a repeat occurrence. These women are recommended to consult their physician for prescriptions for the higher dose (4 mg) of folic acid to be taken one month prior to conception through the third month of pregnancy. They would also be wise to supplement at the newly recommend low dose RDA of 0.4 mg when using contraception and not planning pregnancy.

The above universal dietary supplementation would lower the rate of birth defects such as anencepehally and spina bifida by at least 50%.

Public health has been called "the successful implementation of what is known to be effective." The knowledge exists to promulgate effective policy to prevent over half of the NTD's born, as well as cardiovascular events in 30,000 men and 18,000 in women each year. ^(9.) Yet the general public cannot be counted on to voluntarily take daily vitamin supplementation. Long term public health policy should address child bearing age women as well as large segments of the adult population of America. Many argue that public policy should become universal dietary fortification, to the levels of the doses shown to be preventive of NTD's. Fortunately folate is water soluble and could be added to grain products, just as iron and trace elements are added to white flour. Folic acid is already added to some brands of dry breakfast cereals.

There is a theoretical risk in universal fortification of diet with folic acid. Megaloblastic anemia, the presenting sign of Pernicious Anemia, would be masked by high level folate supplementation. ^(10.) Later, irreversible peripheral neuropathy would become the first sign of Pernicious Anemia. The number of cases which would be hidden by fortification is unknown. However, it has been proposed that low level folate in combination with B12 might prevent both deficiencies.

The Food and Drug administration (FDA) has promulgated new rules requiring that folic acid "be added to specific flour, breads and other grains. These foods were chosen because they have a long history of being successful vehicles for improving nutrition to reduce the risk of classic nutrient deficiency diseases." ^(11.) These rules take effect in 1998, and will include most enriched breads, flours, corn meals, rice, noodles, macaroni and other grain products. Fortification will range from 0.43 to 1.4 mg per pound of product. These levels will allow the daily intake from all sources to remain below the recommended upper limit of 1 mg per day, considered safe for all population groups.

In the mean time, eat your green vegetables and other high folate foods...and take your daily vitamin with folic acid.

At the Spina Bifida Program at CDRC it is our hope that current general and specific dietary supplementation will be observed by all women. We are pleased that shortly a universal fortification of grain, products, though perhaps only minimal, will soon be instituted.

REFERENCES

(1.) Yen IH, Muin JK, Erickson JD, James LM, Waters GD, Berry RJ. The changing epidemiology of Neural Tube Defects: United States, 1968-1989. American Journal of Diseases of Childhood Vol 146: 857-861. 1992.

(2.) Economic burden of spina bifida--United States, 1980-1990. Morbidity and Mortality Weekly Report Vol. 38, No. 15, p. 264-267. 1991.

(3.) Smithells RW, Sheppard S, Schorah CJ. Vitamin deficiencies and neural tube defects. Archives Diseases of Childhood Vol 51: 944-950. 1976.

(4.) Recommendations for the use of folic acid to reduce the number of cases of Spina Bifida and other neural tube defects. Morbidity and Mortality Weekly Report, Vol 41, No. RR-14, p 1-7. 1992.

(5.) Prevention of neural tube defects: Results of the Medical Research Council Vitamin Study. The Lancet Vol 338, p 131-137. 1991.

(6.) Czeizel AE, Dudas I. Prevention of the first occurrence of neural-tube defects by periconceptional vitamin supplementation. The New England Journal of Medicine Vol 327 No. 26, p. 1832-1835. 1992.

(7.) van der Put NM, Steegers-Theunissen R, Frost P, et al. Mutated methylenetetrahydrofolate reductase as a risk factor for spina bifida. The Lancet Vol 346 p. 107-1071. 1995.

(8.) Whitehead AS, Gallagher P, Mills JL, et al. A genetic defect in 5,10 methylenetetrahydrofolate reductase in neural tube defects. Quarterly Journal of Medicine Vol 88, p.763-766. 1995.

(9.) Selhub J, Jacques PF, Bostom AG, et al. Association between plasma homocysteine concentrations and extracranial carotid-artery stenosis. New England Journal of Medicine. Vol 332. No. 5, p.286-291. 1995.

(10.) Williams RD. FDA proposes Folic Acid fortification. U.S. Food and Drug Administration, Office of Public Affairs, FDA Consumer, May 1994.

(11.) Folic Acid fortification. U. S. Food and Drug Administration, Office of Public Affairs, Fact Sheet, February 29, 1996.The Lancet Vol 338, p 131-137. 1991.