Vitamin B9 // Folic Acid

Disease risk reduction

Neural tube defects (NTD)

Neural tube defects (NTD) cause crippling birth defects, which are sometimes fatal. They come about between the 21st and 27th days of the embryo’s development when a lot of women do not even know they are pregnant (5).

When expectant mothers take vitamin B9 (folic acid) supplements combined with a varied diet starting about one month before, and going on one month after conception, randomized controlled trials have shown 60–100% reductions in cases of NTD (6, 7, 8). Folic acid supplementation showed also protective effects on the risk of preterm delivery and small for gestational age birth in a systematic review and meta-analysis (56).

Due to these results and in order to prevent NTD, many health authorities recommend that all women capable of becoming pregnant take 400 micrograms (mcg) of folic acid a day. All women of childbearing age are recommended to do this because the embryo needs sufficient folic acid at a very early stage in pregnancy and because many pregnancies are unplanned. For pregnant women intake of 600 μg DFE/day (DFE=dietary folate equivalents) are recommended from EFSA, WHO and IOM (54)

Additional complications pertaining to pregnancy

Other types of birth defect like various heart problems and limb deformities may also be avoided by sufficient vitamin B9 (folate) intake. However, these findings are not as emphatically or consistently supported as those for NTD prevention (9).

An increased risk of low birth weights, increased occurrence of miscarriage, premature delivery, and complications such as preeclampsia and placental abruption have been linked to low levels of folate in the diet during pregnancy  (10).

Therefore, even once the neural tube is closed, it is sensible to continue folic acid intake throughout pregnancy so that the risk of other pregnancy complications is reduced.

Cardiovascular disease

Homocysteine in relation to cardiovascular disease

That even slightly elevated blood homocysteine levels increase the risk of cardiovascular diseases has been shown by over 80 studies (4). When observational studies on blood homocysteine and vascular disease were analyzed, they demonstrated that a sustained reduction in blood plasma homocysteine of only 1 micromole/l resulted in about a 10% risk reduction (11).

A blood homocysteine level of under 10 micromoles/l is linked to a lower risk of cardiovascular disease, according to most studies, and this also represents a sensible treatment goal for people at high risk (12). However, it is yet unclear whether the risk of developing cardiovascular disease is reduced by lowering homocysteine levels.     

Homocysteine and vitamin B9

A link has been demonstrated between diets rich in vitamin B9 (folate) and a reduced risk of cardiovascular disease. Finnish men whose diet contained the most folate were 55% less likely to have an acute coronary event (e.g., ‘myocardial infarction’) compared to those who consumed the least dietary folate, according to a study that tracked 1,980 participants for ten years (13).

It has been shown that homocysteine levels can be lowered by increasing vitamin B9 (folate) consumption. Twenty-five randomized controlled trials were examined and the meta-analysis demonstrated that the most effective way to reduce plasma homocysteine levels was with supplementation of 0.8 mg folic acid every day. 60% and 90% reductions in plasma homocysteine were linked to a daily intake of 0.2 mg and 0.4 mg folic acid respectively (14).

If there is no coexisting vitamin B12 or vitamin B6 deficiency, the most effective way of lowering basal blood homocysteine levels has been shown to be folic acid supplementation.

It is still not clear whether or not increasing folic acid intake decreases the risk of cardiovascular diseases, even though increasing vitamin B9 intake has been shown to decrease homocysteine levels. However, taking 2.5 mg folic acid, 50 mg vitamin B6, and 1 mg vitamin B12 every day over a five-year period reduces homocysteine levels, as well as the risk of having a stroke, as shown by an analysis of the randomized controlled Heart Outcomes Prevention Evaluation 2 (HOPE 2), which involved 5,522 adults with a history of cardiovascular disease. It did not show a reduction in the severity of strokes or the disability resulting from one (15).

Supplementation with folic acid on its own and in conjunction with vitamin B6 and vitamin B12 was not shown to have an effect on coronary heart disease, strokes, or any cause of death despite a 13–52% reduction in plasma homocysteine concentrations,  according to a meta-analysis taking into account 12 randomized controlled trials (encompassing data from 16,958 people with a history of cardiovascular or kidney disease) (16).

Supplementation with folic acid on its own and in conjunction with vitamin B6 and vitamin B12 was shown to cause a decrease in the risk of stroke of 18% in a meta-analysis carried out of eight intervention studies in 16,841 people. A more recent meta-analysis in patients could show that folic acid supplementation could reduce and effectively prevent the risk of stroke (55, 57). Trials with treatment periods of over 36 months, a reduction in the concentration of homocysteine of more than 20%, and participants with no history of stroke were all factors that showed a greater positive effect (17).

Possible reasons for the mixed results of the studies include: 

  1. Elevated blood homocysteine levels may be a consequence rather than a cause of cardiovascular disease.
  2. The duration of the trials published to date (less than five years) may not be sufficient to reverse the hypothesized damage inflicted by elevated blood homocysteine, which is typically persistent (‘chronic’).
  3. Over-estimation of a possible treatment effect based on earlier epidemiological studies resulted in intervention trials, which may have included far too few individuals to provide a good basis for testing potential effects.
  4. The introduction of mandatory fortification of food with vitamins in the U.S., Canada and Australia during the 1990s resulted in lower than expected effects of supplementation, which may not have been shown by studies that were too small. 

Further clinical trials will probably provide more certainty as to whether or not vitamin B9 (folic acid) can be effectively applied for the prevention or treatment of heart disease.

Alzheimer's disease and cognitive function

Vitamin B9 (folate) is vital for maintaining normal cognitive function due to its role in nucleic acid synthesis and ‘methylation reactions’ (see Health Functions). Links have been noted between reduced folate levels and cognitive impairment in elderly people (27).

Participants in a large cross-sectional study with lower serum folate levels were more likely to suffer from dementia and depression, and were more likely to have to be institutionalized. However, these results could be explained by the poorer nutritional status of institutionalized elderly people and those suffering from dementia. The study group consisted of elderly Canadians. Another study observing 30 elderly nuns living in the same convent, who all consumed the same diet and whose lifestyles were very alike, demonstrated a strong link between low blood folate levels and the degree of deterioration due to Alzheimer's disease (28).

Some studies have presented conflicting results as to whether folate levels affect the risk of Alzheimer's (29, 30, 31).

Alzheimer's disease and dementia have been linked with slightly increased levels of homocysteine combined with reduced vitamin B9 (folate) and vitamin B12 levels. Decreased serum levels of vitamin B12 (under 150 picomoles (pmol)/L) or vitamin B9 (under 10 nanomoles (nmo)l/L) can doube the risk of Alzheimer’s disease (32). This was found by a study covering 370 elderly men and women for three years. In another study, a group of 1,092 men and women without dementia were observed for approximately a decade. Those of them with higher plasma homocysteine levels at baseline (over 14 micromoles/liter) had double the risk of Alzheimer's and dementia (33).

Authored by Dr Peter Engel in 2010, reviewed and revised by  Angelika Friedel on 29.06.2017 

A systematic review and meta-analysis carried out more recently has shown that more clinical trials in this field are necessary. The study could show a positive effect on memory by supplementing B-vitamins in mild cognitive impairment patients, but no effect on general cognitive function and attention (58).

A single center randomized controlled trial in China showed in Alzheimer patients a positive effect of folic acid supplementation (59).

Cancer

Vitamin B9 (folate) intake may well have a beneficial effect on DNA repair and gene expression since researchers think that cancer is generally caused by damage to DNA over and above the body’s continuous DNA repair combined with, or alternatively by, inappropriate gene expression (2).

There have been some reassuring results from studies on the link between folate and cancer prevention, although a lot of the studies have been at odds on the subject.

Breast cancer

There have been no conclusive results from clinical studies examining possible links between vitamin B9 (folate) intake and breast cancer risk reduction (23).

Increasing folate intake may diminish the risk of breast cancer in women who regularly drink alcohol, as suggested by two prospective studies (2425, 26). Increased risk of breast cancer in women has been linked to moderate alcohol consumption in a few studies. 

No link was found between folic acid and breast cancer in women who consumed less than one alcoholic drink per day in a prospective study of over 88,000 nurses. Conversely, as soon as alcohol intake exceeded one drink a day, vitamin B9 (folic acid) intake of 600 micrograms (mcg) a day or more reduced the risk of breast cancer by a half compared with women who received under 300 mcg folic acid per day (26).

A systematic review and meta-analysis with a total of 744 068 participants and 26 205 breast cancer patients could reveal a possible preventive effect of folic acid against breast cancer risk, especially when alcohol consumption was higher (60). Taken together, more studies are needed to link folate intake with beneficial effects for breast cancer and to set the dose and timing of folate supplementation. 

Colorectal cancer

meta-analysis of seven cohort and nine case-control studies showed that the risk of colorectal cancer was increased by vitamin B9 (folate) from foods, yet total folate from food and supplements were not linked to colorectal cancer (18). The authors conceded that something could have disrupted the results since the collected data were from disparate sources and very different in character. 

Alcohol consumption limits the absorption and metabolism of folate in the body (5). Increased colorectal cancer risk has been linked to comparatively low folate intake and high alcohol consumption in certain observational studies (1920). A prospective study of over 45,000 male health professionals demonstrated that consuming two or more alcoholic drinks daily doubled the incidence of colon cancer. Low folate consumption in conjunction with high alcohol intake showed an even greater incidence of colorectal cancer. Interestingly though, participants who consumed more alcohol but also consumed 650 micrograms (mcg) or more of folate per day did not present an increased incidence of colorectal cancer (21).

Despite the apparent benefits of vitamin B9 (folate) regarding colorectal cancer protection, high doses of supplemental folic acid may actually increase the speed at which tumors grow in patients with cancer. One trial in patients with a history of colon cancer found a link between supplementation of 1 mg/day folic acid (over double the RDA) and a tendency toward advanced colorectal lesions, as well as a considerably increased incidence of more than three colorectal adenomas (22). An increased incidence of tumors in other parts of the body, particularly the prostate, was also linked to folic acid supplementation in this study. 

Results from observational studies on high doses of folate and cancer have proven inconclusive so more studies and trials are required.

Authored by Dr Peter Engel in 2010, reviewed and revised by  Angelika Friedel on 29.06.2017