Vitamin B6, folic acid, and vitamin B12 all play a role in converting homocysteine to other substances within the body. By so doing, they consistently lower homocysteine levels in research trials,^1,2,3 a finding that is now well accepted. Several studies have used (and some doctors recommend) 400–1,000 mcg of folic acid per day, 10–50 mg of vitamin B6 per day, and 50–300 mcg of vitamin B12 per day.

Of these three vitamins, folic acid supplementation lowers homocysteine levels the most for the average person.^4,5 It also effectively lowers homocysteine in people on kidney dialysis.⁶ In 1996, the FDA required that all enriched flour, rice, pasta, cornmeal, and other grain products contain 140 mcg of folic acid per 3½ ounces.⁷ This level of fortification has led to a measurable decrease in homocysteine levels.⁸ However, even higher levels of food fortification with folic acid have been reported to be more effective in lowering homocysteine,⁹ suggesting that the FDA-mandated supplementation is inadequate to optimally protect people against high homocysteine levels. Therefore, people wishing to lower their homocysteine levels should continue to take folic acid supplements despite the FDA-mandated fortification program.

Several studies and clinical trials have shown that 50% or more of NTDs can be prevented if women consume a folic acid-containing supplement before and during the early weeks of pregnancy.^10,11 The United States Department of Public Health, the Centers for Disease Control and Prevention (CDC), and the March of Dimes recommend that all women who are capable of becoming pregnant supplement with 400 mcg folic acid daily. Daily supplementation prior to pregnancy is necessary because most pregnancies in the United States are unplanned¹² and the protective effect of folic acid occurs in the first four weeks of fetal development,¹³ before most women know they are pregnant.

For women who have had a previous NTD-affected pregnancy, the CDC recommends daily supplementation with 4,000 mcg per day of folic acid. In a preliminary study, this amount of supplemental folic acid before and during early pregnancy resulted in a 71% reduction in the recurrence rate of NTDs.¹⁴

Most doctors, many other healthcare professionals, and the March of Dimes recommend that all women of childbearing age supplement with 400 mcg per day of folic acid. Such supplementation could protect against the formation of neural tube defects (such as spina bifida) during the time between conception and when pregnancy is discovered.

The requirement for the B vitamin folic acid doubles during pregnancy, to 800 mcg per day from all sources.¹⁵ Deficiencies of folic acid during pregnancy have been linked to low birth weight¹⁶ and to an increased incidence of neural tube defects (e.g., spina bifida) in infants. In one study, women who were at high risk of giving birth to babies with neural tube defects were able to lower their risk by 72% by taking folic acid supplements prior to and during pregnancy.¹⁷ Several preliminary studies have shown that a deficiency of folate in the blood may increase the risk of stunted growth of the fetus.^{18,19,20,21,22,23,24,25} This does not prove, however, that folic acid supplementation results in higher birth weights. Although some trials have found that folic acid and iron, when taken together, have improved birth weights,^26,27,28,29 other trials have found supplementation with these nutrients to be ineffective.^30,31,32

The relationship between folate status and the risk of miscarriage is also somewhat unclear. In some studies, women who have had habitual miscarriages were found to have elevated levels of homocysteine (a marker of folate deficiency).^33,34,35,36 In a preliminary study, 22 women with recurrent miscarriages who had elevated levels of homocysteine were treated with 15 mg per day of folic acid and 750 mg per day of vitamin B6, prior to and throughout their next pregnancy. This treatment reduced homocysteine levels to normal and was associated with 20 successful pregnancies.³⁷ It is not known whether supplementing with these vitamins would help prevent miscarriages in women with normal homocysteine levels. As the amounts of folic acid and vitamin B6 used in this study were extremely large and potentially toxic, this treatment should be used only with the supervision of a doctor.

In other studies, however, folate levels did not correlate with the incidence of habitual miscarriages.^38,39,40

Preliminary⁴¹ and double-blind⁴² evidence has shown that women who use a multivitamin-mineral formula containing folic acid beginning three months before becoming pregnant and continuing through the first three months of pregnancy have a significantly lower risk of having babies with neural tube defects (e.g., spina bifida) and other congenital defects.

In addition to achieving significant protection against birth defects, women who take folic acid supplements during pregnancy have been reported to have fewer infections, and to give birth to babies with higher birth weights and better Apgar scores. ¹⁹ (An Apgar score is an evaluation of the well-being of a newborn, based on his or her color, crying, muscle tone, and other signs.) However, if a woman waits until after discovering her pregnancy to begin taking folic acid supplements, it will probably be too late to prevent a neural tube defect.

Folic acid, sometimes called vitamin B9, is needed along with vitamins B6 and B12 for healthy homocysteine metabolism. Elevated homocysteine levels have been associated with a range of chronic cardiovascular and neurological diseases.⁴³ A meta-analysis pooled findings from 18 randomized controlled trials with a combined total of over 21,000 participants with type 2 diabetes. The analysis found folic acid supplementation lowered fasting blood glucose levels and reduced insulin resistance, but had no discernible effect on HbA1c, a marker of long-term blood glucose control.⁴⁴

Meta-analyses of studies have found high homocysteine levels are correlated with increased risk of diabetic retinopathy (damage to the visual center of the eye) and nephropathy (kidney damage).^45,46 Because folic acid supplementation can lower high homocysteine levels in people with type 2 diabetes, it may be protective.⁴⁷ In a preliminary trial, a B vitamin supplement providing 6 mg of methylfolate (the active form of folic acid), along with 70 mg of pyridoxal 5-phosphate (active vitamin B6) and 4 mg of methylcobalamin (active vitamin B12), per day improved retinal function and reduced retinal edema in participants with type 2 diabetes-related retinopathy.⁴⁸ Several preliminary and placebo-controlled trials using the same B vitamin supplement indicate this combination may reduce symptoms of neuropathy related to type 2 diabetes.^49,50,51

Most doctors, many other healthcare professionals, and the March of Dimes recommend that all women of childbearing age supplement with 400 mcg per day of folic acid. Such supplementation could protect against the formation of neural tube defects (such as spina bifida) during the time between conception and when pregnancy is discovered.

The requirement for the B vitamin folic acid doubles during pregnancy, to 800 mcg per day from all sources.⁵² Deficiencies of folic acid during pregnancy have been linked to low birth weight⁵³ and to an increased incidence of neural tube defects (e.g., spina bifida) in infants. In one study, women who were at high risk of giving birth to babies with neural tube defects were able to lower their risk by 72% by taking folic acid supplements prior to and during pregnancy.⁵⁴ Several preliminary studies have shown that a deficiency of folate in the blood may increase the risk of stunted growth of the fetus.^{55,56,57,58,59,60,61,62} This does not prove, however, that folic acid supplementation results in higher birth weights. Although some trials have found that folic acid and iron, when taken together, have improved birth weights,^63,64,65,66 other trials have found supplementation with these nutrients to be ineffective.^67,68,69

The relationship between folate status and the risk of miscarriage is also somewhat unclear. In some studies, women who have had habitual miscarriages were found to have elevated levels of homocysteine (a marker of folate deficiency).^70,71,72,73 In a preliminary study, 22 women with recurrent miscarriages who had elevated levels of homocysteine were treated with 15 mg per day of folic acid and 750 mg per day of vitamin B6, prior to and throughout their next pregnancy. This treatment reduced homocysteine levels to normal and was associated with 20 successful pregnancies.⁷⁴ It is not known whether supplementing with these vitamins would help prevent miscarriages in women with normal homocysteine levels. As the amounts of folic acid and vitamin B6 used in this study were extremely large and potentially toxic, this treatment should be used only with the supervision of a doctor.

In other studies, however, folate levels did not correlate with the incidence of habitual miscarriages.^75,76,77

Preliminary⁷⁸ and double-blind⁷⁹ evidence has shown that women who use a multivitamin-mineral formula containing folic acid beginning three months before becoming pregnant and continuing through the first three months of pregnancy have a significantly lower risk of having babies with neural tube defects (e.g., spina bifida) and other congenital defects.

In addition to achieving significant protection against birth defects, women who take folic acid supplements during pregnancy have been reported to have fewer infections, and to give birth to babies with higher birth weights and better Apgar scores. ⁵⁶ (An Apgar score is an evaluation of the well-being of a newborn, based on his or her color, crying, muscle tone, and other signs.) However, if a woman waits until after discovering her pregnancy to begin taking folic acid supplements, it will probably be too late to prevent a neural tube defect.

Large amounts of folic acid—10 mg per day—have been shown to improve the abnormal Pap smears of women who are taking birth control pills.⁸⁰ Folic acid does not improve the Pap smears of women who are not taking oral contraceptives.^81,82 High blood levels of folate (the food form of folic acid) have been linked to protection against the development of cervical dysplasia but these higher levels may only be a marker for eating more fruit and vegetables.^83,84